Treatment of viral infections using prodrugs of 2′,3-dideoxy,3′-fluoroguanosine

ABSTRACT

A method of treating HBV or HIV infections comprising administering to an individual an effective amount of the compound of formula IId′: 
                 
         wherein R 2  is the residue of an aliphatic L-amino acid, p is 0, 1, or 2-20, and q is 0, or a pharmaceutically acceptable salt thereof.

This application is a divisional of application Ser. No. 09/249,317,filed on Feb. 12, 1999 now U.S. Pat. No. 6,958,772, the entire contentsof which are hereby incorporated by reference and for which priority isclaimed under 35 U.S.C. § 120; and this application claims priority ofapplication Ser. Nos. 9803438-2, 9800452-6, 9801216-4, 9800469-0,9803438-2, 98/7267, PCT/SE98/01467 filed in Sweden, Sweden, Sweden,Sweden, Sweden, South Africa and United States on Oct. 7, 1998, Feb. 13,1998, Apr. 3, 1998, Feb. 16, 1998, Aug. 13, 1998 and Aug. 14, 1998 under35 U.S.C. § 119.

TECHNICAL FIELD

This invention relates to the field of prodrugs, that is novelderivatives of otherwise known and proven drugs which release that drugin active or pro-active form in vivo. The enzymatic and/or chemicalcleavage of the compounds of the present invention occurs in such amanner that the parent drug is released and the moiety or moieties splitoff remain non-toxic or are metabolized so that non-toxic or acceptableamounts of metabolic products are produced. The present compounds thusmodify the in vivo availability of the parent compound compared to whatwould be the case if the parent compound was to be administered itself.For instance the prodrugs of the invention may give higherbioavailabities, varied bioavailability kinetics or bioavailabilitieswith a decreased interpersonal spread.

A first aspect of the invention relates to the field of nucleosideanalogues, such as antivirals including inhibitors of retroviral reversetranscriptase and the DNA polymerase of Hepatitis B Virus (HBV). Theinvention provides novel compounds with favourable pharmaceuticalparameters, methods for their preparation, pharmaceutical compositionscomprising these compounds and methods employing then for the inhibitionof viral and neoplastic diseases including HBV and HIV.

BACKGROUND TO THE INVENTION

International patent application no. WO 88/00050 describes theantiretroviral and anti-HBV activity of a series of 3′-fluorinatednucleosides, including the compounds 2′,3′-dideoxy, 3′-fluoroguanosine(FLG) and 3′-fluorothymidine (FLT). The latter compound underwentclinical evaluation as an anti-HIV agent and although its antiviralactivity and pharmacokinetics were good, it showed unexpected toxicity(Flexner et al, J Inf Dis 170(6) 1394-403 (1994)). The former compoundFLG is very active in vitro however the present inventors have detectedthat its bioavailability is so poor—around 4%—that the in vivo utilityof the compound has thus far been limited to intaperitoneally orsubcutaneously administered animal models.

U.S. Pat. No. 4,963,662 discloses generically a series of 3′-fluorinatednucleosides and corresponding triphosphates and specifically describesthe preparation of the 5′-O-palmitoyl derivative of FLT, withoutreporting any improvement in bioavailability. International patentapplication WO 93 13778 describes FLG derivatives modified at the6-position of the base, in particular with n-propoxy, cyclobutoxy,cyclopropanylamino, piperdino or pyrrolidino. International patentapplication no. 93 14103 describes FLG derivatives where the oxygen atthe guanine 6-position is replaced with amino, ether, halo orsulphonate.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with one aspect of the invention there are providedcompounds of the formula I:

wherein:

-   R₁ is selected from hydroxy, amino or carboxy; optionally having    esterified/amide bonded thereon a C₄-C₂₂ saturated or unsaturated,    optionally substituted fatty acid or alcohol, or an aliphatic    L-amino acid;-   R₂ is the residue of an aliphatic L-amino acid;-   L₁ is a trifunctional linker group;-   L₂ is absent or a difunctional linker group;    and pharmaceutically acceptable salts thereof.

The invention further provides pharmaceutical compositions comprisingthe compounds and salts of formula I and pharmaceutically acceptablecarriers or diluents therefor. Additional aspects of the inventionprovide methods for the inhibition of HBV and retroviruses such as HIV,comprising bringing a compound or salt of the formula I into contactwith a retrovirus or HBV, for example by administering an effectiveamount of the compound or salt to an individual afflicted with aretrovirus or HBV. The invention also extends to the use of thecompounds or salts of formula I in therapy, for example in thepreparation of a medicament for the treatment of retroviral or HBVinfections.

In treating conditions caused by retroviruses such as HIV, or HBV, thecompounds or salts of formula I are preferably administered in an amountof 50 to 1.500 mg once, twice or three times per day, especially 100 to700 mg twice or thrice daily. It is desirable to achieve serum levels ofthe active metabolite of 0.01 to 100 μg/ml, especially 0.1 to 5 μg/ml.

Where R₁ is a fatty acid residue, it preferably has in total an evennumber of carbon atoms, advantageously decanoyl (C₁₀), lauryl (C₁₂),myristoyl (C₁₄), palmitoyl (C₁₆), stearoyl (C₁₈), eicosanoyl (C₂₀) orbehenoyl (C₂₂). The fatty acid preferably has in total 10 to 22, andmore preferably 16 to 20 carbon atoms, especially 18. The fatty acid maybe unsaturated and have one to three double bonds, especially one doublebond. Unsaturated fatty acids preferably belong to the n-3 or n-6series. Convenient unsaturated R₁ groups include those derived from themonounsaturated acids myristoleic, myristelaidic, palmitoleic,palmitelaidic, n6-octadecenoic, oleic, elaidic, gandoic, erucic,brassidic acids or multiply unsaturated fatty acids such as linoleic,γ-linolenic, arachidonic acid and α-linolenic acid. Preferably, however,R1 as a fatty acid is saturated as these compounds tend to have superiorstability and shelf life.

R₁ as fatty alcohol residue preferably corresponds to one of the abovedescribed fatty acids. Alternatively the fatty alcohol may compriseresidues of shorter alcohols, such as methanol, ethanol or propanol.

R₁ as a saturated or unsaturated fatty acid or alcohol may optionally besubstituted with up to five similar or different substituentsindependently selected from the group consisting of hydroxy, C₁-C₆alkyl, C₁-C₆ alkoxy C₁-C₄ alkoxy C₁-C₆ alkyl, C₁-C₆ alkanoyl, amino,halo, cyano, azido, oxo, mercapto and nitro, and the like. Suitablealiphatic amino acids for R₂ and, if present R₁, include L-alanine,L-leucine, L-isoleucine and most preferably L-valine. For ease ofsynthesis it is preferred that both R₂ and R₁ are residues of aliphaticamino acids, preferably the same residue.

The expression trifunctional in the context of the first linker group L₁means that the linker has at least three functional groups, including atleast two functional groups derived from respective hydroxy, amine orcarboxyl groups, the amine and hydroxy function(s) being available foresterification/amide bonding with the carboxy functions of R₁ and R₂whereas a carboxy function(s) on the linker is available for amidebonding with the free α-amine function of R₂, or R₁ as the case may be,or esterification with R₁ as a fatty alcohol. Where R₁ itself defines anhydroxy, amine or carboxy group, the hydroxy group being presentlyfavoured of the three, one of said functions on the trifunctional linkersimply comprises this hydroxy, amine or carboxy group.

The trifunctional linker further comprises a third functional group forlinkage with either the optional second linker group L₂ illustrated inmore detail below, or the hydroxy group at the 5′ position of the mothernucleoside, such as 2′,3′-dideoxy-3′-fluoroguanosine. Appropriate thirdfunctional groups will depend on the nature of the cooperating functionon optional linker group L₂, if present, and may include amino, hydoxy,carbonyl, sulfonyl, phosphoryl, phosphonyl, carbamoyl and the like. IfL₂ is absent, this third functional group on first linker L₁ willtypically comprise a carboxyl function which can esterify with the 5′-Ogroup of the nucleoside analogue.

Preferably the functional groups on the trifunctional linker whichcooperate with R₁ and R₂ are hydroxyl functions and the linkage is anester linkage with the carboxyl functions of an R₁ fatty acid, ifpresent, and R₂. A further preferred embodiment comprises a free hydroxygroup as R₁ and an hydroxyl function on the linker esterified to thecarboxy function of R₂. An alternative embodiment comprises an(optionally protected) carboxyl group as R₁ and an hydroxyl function onthe linker esterified to a carboxy function on R₂.

Useful trifunctional L₁ group, especially for esterifying directly tothe nucleoside include linkers of the formula IIa or IIb:

where A and A′ define a respective ester linkage between an hydroxy onthe linker and the carboxy on R₁ or R₂ or an ester linkage between acarboxy on the linker and the hydroxy on R₁ as a fatty alcohol, or anamide linkage between an amine on the linker and a carboxy on R₁ or R₂,or an amide linkage between a carboxy on the linker and an amine on R₁or R₂, or one of A and A′ is as defined and the other is hydroxy, aminoor carboxy in the event that R₁ itself is a free hydroxy, amino orcarboxy group.

-   -   Rx is H or C₁-C₃ alkyl,    -   T is a bond, —O— or —NH—;    -   Alk is absent, C₁-C₄ alkyl or C₂-C₄ alkenyl, optionally        substituted as described above; and    -   m and n are independently 0, 1 or 2.

In a preferred embodiment of this aspect of the invention, the R₁ or R₂groups are each esterified to a respective one of the leftmostfunctional hydroxy groups (viz A and A′) of Formula IIa, while thecarbonyl moiety to the right is esterified, optionally via a secondlinker group L₂, to the 5′-O-group of the nucleoside.

Alternatively the L₁ group may comprise a linker of the formula IIb:

-   where Ar is a saturated or unsaturated, preferably monocyclic carbo-    or heterocycle with 5 or 6 ring atoms; and    -   A, A′, T, Alk, m and n are as defined above.

In Formula IIb, Ar is preferably an aromatic group such as pyridine orespecially phenyl, such as aromatic moieties wherein the arms bearingthe R₁ and R₂ groups are respectively para and ortho, meta and ortho,both ortho, or preferably para and meta, both para or both meta to theremainder of the linker.

In formulae IIa and IIb, the following combinations of m, n and Alk arepresently favoured:

m n Alk 1 0 absent 1 0 methylene 1 0 ethylene 1 1 absent 1 1 methylene 11 ethylene 1 1 propylene 1 2 absent 1 2 methylene 1 1 ethenylene 1 1propenylene

As R₁ and R₂ may have different structures, it will be apparent thatmany L₁ groups, particularly those of formula IIa, will define chiralstructures and the invention includes all enantiomers thereof, asracemates or as preparations of >80%, preferably >95% enantiomericallypure compound.

A favoured structure within formula IIa has the formula:

which breaks down in vivo to the nature identical glyceric acid.Particularly preferred are compounds derived from D-glyceric acid.

Thus preferred compounds of formula I include:

-   5′-O-[(S,R)2,3-bis-(L-valyloxy)-propionyl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[(S,R)2,3-bis-(L-isoleucyloxy)-propionyl]-2′,3′-dideoxy-3′-fluoroguanosine,    and most preferably-   5′-O-[(R)2,3-bis-(L-valyloxy)-propionyl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[(R)2,3-bis-(L-isoleucyloxy)-propionyl]-2′,3′-dideoxy-3′-fluoroguanosine;    and their pharmaceutically acceptable salts.

A particularly preferred group of trifunctional linkers compriseglycerol derivatives of the formula IIc

where A is hydrogen, the acyl residue of an aliphatic L-amino acid esteror the acyl residue of a fatty acid ester, A′ is the acyl residue of analiphatic amino acid residue and D is a C₂-C₅ saturated or unsaturateddicarboxylic acid residue. Trifunctional linkers of the formula IIc arehydrolysed or otherwise break down in vivo to release the natureidentical compounds glycerol, the L-amino acid, the fatty acid (ifpresent) and the dicarboxylic acid, each of which are generally safelymetabolised and/or excreted by the body. Preferably A and A′ are bothresidues of an aliphatic amino acid, most preferably the same residue,particularly residues of L-valine or L-isoleucine.

In the event that the dicarboxylic acid moiety in the derivative offormula IIc is esterified directly to the 5′ hydroxy function (orequivalent) on the nucleoside, an alternative analysis would be todefine the glycerol moiety as trifunctional linker L₁ and thedicarboxylic acid moiety as difunctional linker L₂.

Particularly preferred dicarboxylic acid residues include those derivedfrom oxalic, malonic, tartronic, succinic, maleic, fumaric, malic,tartaric, glutaric, glutaconic, citraconic, itaconic, ethidine-malonic,mesaconic, adipic, allylmalonic, propylidenemalonic, hydromuconic,pyrocinchonic and muconic acids and the like. The dicarboxylic acidresidue may be optionally substituted, for example with the substituentslisted above in respect of R₁ as a fatty acid. Hydroxy substituents canin turn be esterified with a further L-amino acid or fatty acid residue.

Several of the abovementioned dicarboxylic acids can themselves define atrifunctional linker. For instance hydroxy-substituted dicarboxylicacids such as tartaric acid or malic acid offer a number ofconfigurations within the scope of the invention. Taking tartaric acidas an example a carboxyl function is available for esterification withthe 5′-hydroxyl function of a nucleoside (optionally via difunctionallinker L₂). The hydroxy functions are available for esterification withthe respective carboxyl functions of R₂ and an R₁ fatty acid or aminoacid while the remaining carboxy group can be free, or optionallyprotected, for instance with a conventional pharmaceutically acceptableester such as the methyl or ethyl ester. Alternatively the optionalprotection of the free carboxy function can itself comprise an esterwith an R₁ fatty alcohol, with one or both hydroxyl functions beingesterified to R₂:

Favoured linkers of the tartaric acid series above can be genericallydepicted as Formula IIe:

and isomers where R₁ and R₂ are reversed, where R₁ and R₂ are as shownabove, p, q and r are each independently 0 to 5, preferably 0 or 1 andR_(y) is the free acid, an R₁ ester or a conventional pharmaceuticallyacceptable carboxy protecting group, such as the methyl, benzyl orespecially the ethyl ester.

Favoured linkers of the malic series have the formula IIf:

where Ry, p,q and R₂ are as defined above, preferably those where p andq are zero.

Preferred compounds of this aspect of the invention thus include:

-   5′-O-[3-methoxycarbonyl-2-valyloxy-propionyl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[3-benzyloxycarbonyl-2-valyloxy-propionyl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[3-methoxycarbonyl-2-isoleucloxy-propionyl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[3-benzyloxycaxbonyl-2-isoleucyloxy-propionyl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[4-methoxycarbonyl-2,3-bis-valyloxy-butyryl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[4-benzyloxycarbonyl-2,3-bis-valyloxy-butyryl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[4-methoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[4-benzyloxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-2′,3′-dideoxy-3′-fluoroguanosine;    particularly those derived from L-malic acid and L-tartaric acid;    and corresponding derivatives employing conventional    pharmaceutically acceptable esters on the terminal carboxy function.

Particularly favoured compounds include:

-   5′-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-2′,3′-dideoxy-3′-fluoroguanosine,-   5′-O-[4-ethoxycarbonyl-2,3-bisisoloucyloxy-butyryl]-2′,3′-dideoxy-3′-fluoroguanosine,    expecially the isomers derived from L-malic and L-tartaric acid.

In a related alternative aspect of the invention one of R₁ and R₂ isomitted. Representative compounds of this aspect of the inventioninclude those of the formual Ia:

where Alk is optionally substituted C₁-C₄ alkyl or C₂-C₄ alkenyl and R₂is the ester residue of an aliphatic L-amino acid or a fatty acid asdefined for R₁ and R₂ above. Linkers of this aspect of the invention areconveniently prepared from α-hydroxy ω-carboxylic acids such as carbonicacid, glycollic acid, hydroxypropanoic acid, hydroxybutyric acid,hydroxyvaleric acid or hydroxycaproic acid.

Representative compounds of Formula Ia include:

-   2′,3′-dideoxy-3′-fluoro-5-O-[3-(L-valyloxy)-propionyl] guanosine-   2′,3′-dideoxy-3′-fluoro-5′-O-[5-(L-valyloxy)-pentanoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5′-O-[6-(L-valyloxy)-hexanoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[3-(L-isoleuclyoxy)-propionyl] guanosine-   2′,3′-dideoxy-3′-fluoro-5′-O-[5-(L-isoleucyloxy)-pentanoyl]    guanosine,-   2′,3′-dideoxy-3′-fluoro-5′-O-[6-(L-isoleucyloxy)-hexanoyl]    guanosine,    and pharmaceutically acceptable salts thereof.

Particularly favoured compounds of formula Ia include:

-   2′,3′-dideoxy-3′-fluoro-5′-O-[4-(L-valyloxy)-butyryl] guanosine; and-   2′,3′-dideoxy-3′-fluoro-5′-O-[4-(L-isoleucyloxy)-butyryl] guanosine    and    pharmaceutically acceptable salts thereof. In these compounds    hydrolysis and removal of the R₂ group in vivo leaves a reactive    terminal radical which will tend to cyclize and prompt the effective    release of the mother nucleoside.

In a related alternative aspect of the invention, R₁ as a fatty acidresidue is itself used as the linker, with the aliphatic L-amino acidresidue of R₂ being esterified/amide bonded to an amino, hydroxy orcarboxy function on the fatty acid alkyl chain, for example on theβ-carbon. In this embodiment the fatty acid of R₁ is esterified directlyon the 5′-hydroxy (or equivalent) function of the nucleoside, generallywith the R₂ group already esterified/amide bonded thereon.Alternatively, the functionalised fatty acid (the carboxy/hydroxy/aminofunction being appropriately protected) can be first esterified to thenucleoside and deprotected prior to coupling with R₂. Linkers inaccordance with a preferred embodiment of this aspect have the formulaIId:

where R₂ is the residue of an aliphatic L-amino acid and, p is 0, 1 or2-20 (optionally including a double bond) and q is 0-5, preferably 0.Representative compounds include:

-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-butyryl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-hexanoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-octanoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-decanoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-dodecanoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-myristoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-palmitoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-stearoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-docosanoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-eicosanoyl] guanosine-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-butyryl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-hexanoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-octanoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-decanoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-dodecanoyl]    guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-myristoyl]    guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-palmitoyl]    guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-stearoyl] guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-docosanoyl]    guanosine,-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-eicosanoyl]    guanosine,    and the corresponding n-3 and n-6 monounsaturated analogues, such as    6 or 9 octadecenoyl derivatives.

In formula IId, p and q are preferably 0, thus defining lactic acidderivatives, preferably L-lactic acid derivatives, such as

-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-propionyl] guanosine;    and-   2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-isoleucyloxy)-propionyl] guanosine    and    pharmaceutically acceptable salts thereof, as the breakdown    products, lactic acid and the amino acid are both well accepted    physiologically.

The expression bifunctional in the context of second linker group L₂means that the the linker has two functions enabling it to act a spaceror bridge between the first linker group L₁ and the 5′-O group of thenucleoside. For instance the optional group L₂ may comprise a linker ofthe formula IIIa:

where R₄ and R₄′ are hydrogen or C₁-C₄ alkyl. In formula IIIa, R₄ ispreferably hydrogen, methyl, ethyl or isopropyl and R₄′ is hydrogen.Linkers of formula IIIa are convenient as many nucleosides such as theFLG mother compound must first be phosphorylated by cellular enzymesbefore it can inhibit the viral polymerase. An initial or sequentialhydrolysis of compounds of the invention can release amonophosphorylated nucleoside in vivo which is available for immediateconversion to the di- and triphosphate.

Alternatively the optional bifunctional linker group L₂ may comprise astructure of the formula IIIb:

where R₄ and R₄′ are independently H or C₁-C₄ alkyl.

A still further group of bifunctional linkers have the formula IIIc:

As described above, a preferred group of bifunctional linkers comprisesα,ω-dicarboxylic C₂-C₆ alkyl derivatives, such as succinic acid, whichare optionally substituted (for instance with the substituents definedabove for R₁ as a fatty acid) and/or optionally mono or polyunsaturated,such as n-3 or n-6 monounsaturated. Preferred moieties within this classare listed above.

Although the disclosure above has concentrated on glycerol L₁ groups inconjunction with dicarboxylic L₂ groups, it will be appreciated that awide variety of trifunctional linkers are appropriate with dicarboxylicL₂ groups, for instance structures of the formula IIa and IIb abovelacking the rightmost carbonyl.

The invention further includes double prodrugs comprising R₁(R₂)L₁L₂-derivatives of conventional FLG prodrugs, which conventionalprodrugs release FLG in vivo, such as prodrug derivatives at the 2 and 6positions of the FLG guanine base. Examples of such conventionalFLG-prodrugs include compounds of the formula IV:

where R₁, R₂, L₁ and L₂ are as defined above; and

-   R₃ is H, N₃, NH₂, or OH or a pharmaceutically acceptable ether or    ester thereof; and-   R₃′ is an aromatic bond or hydrogen;

Potential pharmaceutically acceptable esters for R₃ include the fattyacids described in relation to R₁ above, such as stearolyl, oleoyl etcor shorter esters such as acetyl or butyryl. Other potential estersinclude the amino acid derivatives of R₂ or esters of phosphoric acid,such as monophosphate. Alternative esters include the correspondingfatty acid or alkylaryl carbonate, carbamate or sulphonic esters.

Suitable pharmaceutically acceptable ethers for R₃ include C₁-C₆ alkyl,cycloalkyl, C₆-C₁₂ alkaryl such as benzyl or methylpyridyl, any of whichmay be optionally substituted as for R₁ above. Convenient ethers includethose described in the abovementioned WO 93 13778 such as n-propoxy,cyclobutoxy, cyclopropanylamino, piperidino or pyrrolidino and the like.

The invention has thus far been described with reference to themonohydroxylated nucleoside FLG, however it will be apparent thatcorresponding derivatives can be prepared of other monohydroxylatednucleoside analogues, particularly those where the monohydroxy groupcorresponds to the 5′ hydroxy function of a nucleoside. Thus anadditional aspect of the invention provides compounds of the formula Ic:

where R₁, R₂, L₁ and L₂ are as defined above and —O-nuc is the residueof a monohydroxyl bearing D- or L-nucleoside analogue. Representativenucleosides in accordance with this aspect of the invention includeacyclic nucleoside analogues such as acyclovir and cyclic nucleosideanalogues such as ddI (didanosine), ddC (zalcitabine), d4T (stavudine),FTC, lamivudine (3TC), 1592U89(4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol),AZT (zidovudine), DAPD (D-2,6-diaminopurine dioxolane), F-ddA and thelike, each of which are well known in the nucleoside art. A number ofmonohydric L-nucleosides are under development and the invention willalso find utility on this compounds. Compounds within this aspect of theinvention will find utility in the corresponding indications to themother compounds, for instance herpesvirus infections for acyclovirderivatives, HIV for ddI, stavudine, ddC, lamivudine, AZT & 1592U89, HBVfor lamivudine, FTC etc.

A favoured subgroup within Formula Ic comprises derivatives ofmonohydric nucleosides of the formula Ic′:

where A, A′, Alk and O-nuc are as defined above. Formula Ic′ abovedepicts compounds wherein A and A′ depend from the 1 and 3 positions ofthe glycereol moiety and L₂ depends from the glycerol 2 position. Inalternative isomers A and A′ depend 1 and 2 or 2 and 3 and L₂ from 3 or2 respectively.

Representative compounds within this aspect of the invention include;

-   4′-O-[3-((2,3-bis-L-valyloxy)-1-propyloxycarbonyl)propionyl]    acyclovir,-   4′-O-[3-((2-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]    acyclovir,-   4′-O-[3-((2,3-bis-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]    acyclovir,-   4′-O-[3-((2-hydroxy-3-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]    acyclovir,-   4′-O-[3-((1,3-bis-L-valyloxy)-2-propyloxycarbonyl)propionyl]    acyclovir,-   4′-O-[3-((1-hydroxy-3-L-valyloxy)-2-propyloxycarbonyl)propionyl]    acyclovir,-   4′-O-[3-((1,3-bis-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]    acyclovir,-   4′-O-[3-((1-hydroxy-3-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]    acyclovir,-   5′-O-[3-((2,3-bis-L-valyloxy)-1-propyloxycarbonyl)propionyl]    lamivudine,-   5′-O-[3-((2-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]    lamivudine,-   5′-O-[3-((2,3-bis-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]    lamivudine,-   5′-O-[3-((2-hydroxy-3-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]    lamivudine,-   5′-O-[3-((1,3-bis-L-valyloxy)-2-propyloxycarbonyl)propionyl]    lamivudine,-   5′-O-[3-((1-hydroxy-3-L-valyloxy)-2-propyloxycarbonyl)propionyl]    lamivudine,-   5′-O-[3-((1,3-bis-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]    lamivudine,-   5′-O-[3-((1-hydroxy-3-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]    lamivudine,-   5′-O-[3-((2,3-bis-L-valyloxy)-1-propyloxycarbonyl)propionyl] DAPD,-   5′-O-[3-((2-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]    DAPD,-   5′-O-[3-((2,3-bis-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]    DAPD,-   5′-O-[3-((2-hydroxy-3-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]    DAPD,-   5′-O-[3-((1,3-bis-L-valyloxy)-2-propyloxycarbonyl)propionyl] DAPD,-   5′-O-[3-((1-hydroxy-3-L-valyloxy)-2-propyloxycarbonyl)propionyl]    DAPD,-   5′-O-[3-((1,3-bis-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]    DAPD,-   5′-O-[3-((1-hydroxy-3-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]    DAPD,-   5′-O-[3-((2,3-bis-L-valyloxy)-1-propyloxycarbonyl)propionyl]-2′,3′-dideoxyinosine-   5′-O-[3-((2-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]-2′,3′-dideoxyinosine,-   5′-O-[3-((2,3-bis-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]-2′,3′-dideoxyinosine,-   5′-O-[3-((2-hydroxy-3-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]-2′,3′-dideoxyinosine,-   5′-O-[3-((1,3-bis-L-valyloxy)-2-propyloxycarbonyl)propionyl]-2′,3′-dideoxyinosine,-   5′-O-[3-((1-hydroxy-3-L-valyloxy)-2-propyloxycarbonyl)propionyl]-2′,3′-dideoxyinosine,-   5′-O-[3-((1,3-bis-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]-2′,3′-dideoxyinosine,-   5′-O-[3-((1-hydroxy-3-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]-2′,3′-dideoxyinosine,-   5′-O-[3-((2,3-bis-L-valyloxy)-1-propyloxycarbonyl)propionyl]    stavudine,-   5′-O-[3-((2-hydroxy-3-L-valyloxy)-1-propyloxycarbonyl)propionyl]    stavudine,-   5′-O-[3-((2,3-bis-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]    stavudine,-   5′-O-[3-((2-hydroxy-3-L-isoleucyloxy)-1-propyloxycarbonyl)propionyl]    stavudine,-   5′-O-[3-((1,3-bis-L-valyloxy)-2-propyloxycarbonyl)propionyl]    stavudine,-   5′-O-[3-((1-hydroxy-3-L-valyloxy)-2-propyloxycarbonyl)propionyl]    stavudine,-   5′-O-[3-((1,3-bis-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]    stavudine,-   5′-O-[3-((1-hydroxy-3-L-isoleucyloxy)-2-propyloxycarbonyl)propionyl]    stavudine,    the corresponding derivatives of    4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol,    and pharmaceutically acceptable salts thereof.

A preferred group of compound sis based on glyceric acid, including

-   5′-O-[(S)2,3-bis-(L-valyloxy)-propionyl]-stavudine-   5′-O-[(S)2,3-bis-(L-isoleucyloxy)-propionyl]-stavudine;-   5′-O-[(S)2,3-bis-(L-valyloxy)-propionyl]-dideoxyinosine-   5′-O-[(S)2,3-bis-(L-isoleucyloxy)-propionyl]-dideoxyinosine-   5′-O-[(S)2,3-bis-(L-valyloxy)-propionyl]-DAPD-   5′-O-[(S)2,3-bis-(L-isoleucyloxy)-propionyl]-DAPD-   5′-O-[(S)2,3-bis-(L-valyloxy)-propionyl]-lamivudine-   5′-O-[(S)2,3-bis-(L-isoleucyloxy)-propionyl]-lamivudine-   5′-O-[(S)2,3-bis-(L-valyloxy)-propionyl]-acyclovir-   5′-O-[(S)2,3-bis-(L-isoleucyloxy)-propionyl]-acyclovir    and pharmaceutically acceptable salts thereof.

An alternative subset of compounds within this aspect of the inventioncomprise those of the formula Id:

where Rz and Alk are as defined for formula Ia and O-nuc is as definedabove.

Representative compounds of formula Id include

-   4′-O-[4-(L-valyloxy)-propionyl] acyclovir,-   4′-O-[5-(L-valyloxy)-pentanoyl] acyclovir,-   4′-O-[6-(L-valyloxy)-hexanoyl] acyclovir,-   4′-O-[4-(L-isoleucyloxy)-propionyl] acyclovir,-   4′-O-[5-(L-isoleucyloxy)-pentanoyl] acyclovir,-   4′-O-[6-(L-isoleucyloxy)-hexanoyl] acyclovir,-   5′-O-[4-(L-valyloxy)-propionyl] ddI,-   5′-O-[5-(L-valyloxy)-pentanoyl] ddI,-   5′-O-[6-(L-valyloxy)-hexanoyl] ddI,-   5′-O-[4-(L-isoleucyloxy)-propionyl] ddI,-   5′-O-[5-(L-isoleucyloxy)-pentanoyl] ddI,-   5′-O-[6-(L-isoleucyloxy)-hexanoyl] ddI,-   5′-O-[4-(L-valyloxy)-propionyl] stavudine,-   5′-O-[5-(L-valyloxy)-pentanoyl] stavudine,-   5′-O-[6-(L-valyloxy)-hexanoyl] stavudine,-   5′-O-[4-(L-isoleucyloxy)-propionyl] stavudine,-   5′-O-[5-(L-isoleucyloxy)-pentanoyl] stavudine,-   5′-O-[6-(L-isoleucyloxy)-hexanoyl] stavudine,-   5′-O-[4-(L-valyloxy)-propionyl] DAPD,-   5′-O-[5-(L-valyloxy)-pentanoyl] DAPD,-   5′-O-[6-(L-valyloxy)-hexanoyl] DAPD,-   5′-O-[4-(L-isoleucyloxy)-propionyl] DAPD,-   5′-O-[5-(L-isoleucyloxy)-pentanoyl] DAPD,-   5′-O-[6-(L-isoleucyloxy)-hexanoyl] DAPD,-   5′-O-[4-(L-valyloxy)-propionyl] lamivudine,-   5′-O-[5-(L-valyloxy)-pentanoyl] lamivudine,-   5′-O-[6-(L-valyloxy)-hexanoyl] lamivudine,-   5′-O-[4-(L-isoleucyloxy)-propionyl] lamivudine,-   5′-O-[5-(L-isoleucyloxy)-pentanoyl] lamivudine,-   5′-O-[6-(L-isoleucyloxy)-hexanoyl] lamivudine,    and the corresponding derivatives of    4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol.

Particularly preferred compounds within Formula Id include:

-   4′-O-[4-(L-valyloxy)-butyryl] acyclovir,-   4′-O-[3-(L-isoleucyloxy)-butyryl] acyclovir,-   5′-O-[4-(L-valyloxy)-butyryl] ddI,-   5′-O-[3-(L-isoleucyloxy)-butyryl] ddI,-   5′-O-[4-(L-valyloxy)-butyryl] stavudine,-   5′-O-[3-(L-isoleucyloxy)-butyryl] stavudine,-   5′-O-[4-(L-valyloxy)-butyryl] DAPD,-   5′-O-[3-(L-isoleucyloxy)-butyryl] DAPD,-   5′-O-[4-(L-valyloxy)-butyryl] lamivudine,-   5′-O-[3-(L-isoleucyloxy)-butyryl] lamivudine,    and the corresponding derivatives of    4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol;    and pharmaceutically acceptable salts thereof, In these compounds    hydrolysis and removal of the R₂ group in vivo leaves a reactive    terminal radical which will tend to cyclize and prompt the effective    release of the mother nucleoside.

Similarly the invention extends to compounds of the formula If:

where R₁, R₂, R_(y), p, q, r and o-nuc are as defined above.

Favoured compounds of this aspect of the invention include:

-   5′-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-ddI,-   5′-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-ddI,-   5′-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-ddI ,-   5′-O-[4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-ddI,-   4′-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-acyclovir,-   4′-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-acyclovir-   4′-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-aciclovir,-   4′-O-[4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-aciclovir,-   5′-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-DAPD,-   5′-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-DAPD-   5′-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-DAPD,-   5′-O-[4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-DAPD,-   5′-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-stavudine,-   5′-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-stavudine-   5′-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-stavudine,-   5′-O-[3-ethoxycarbonyl-2-valyloxy-propionyl]-lamivudine,-   5′-O-[3-ethoxycarbonyl-2-isoleucyloxy-propionyl]-lamivudine-   5′-O-[4-ethoxycarbonyl-2,3-bis-valyloxy-butyryl]-lamivudine,-   5′-O-[4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyryl]-lamivudine,    and the corresponding malic and tartric derivatives of    4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol    and pharpamceutically acceptable salts thereof; in each case the    isomers derived from L-tartrate and L-malate derivatives being    preferred.

The invention also extends to compounds of the formula Ig

where R₂, p, q and O-nuc are as defined above.

Preferred compounds of formula Ig include:

-   4′-O-[2-(L-valyloxy)-propionyl] acyclovir,-   4′-O-[2-(L-isoleucyloxy)-propionyl] acyclovir-   5′-O-[2-(L-valyloxy)-propionyl] ddI,-   5′-O-[2-(L-isoleucyloxy)-propionyl] ddI,-   5′-O-[2-(L-valyloxy)-propionyl] stavudine,-   5′-O-[2-(L-isoleucyloxy)-propionyl] stavudine-   5′-O-[2-(L-valyloxy)-propionyl] lamivudine,-   5′-O-[2-(L-isoleucyloxy)-propionyl] lamivudine,-   5′-O-[2-(L-valyloxy)-propionyl] DAPD,-   5′-O-[2-(L-isoleucyloxy)-propionyl] DAPD    and the corresponding derivatives of    4-[2-amino-6(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol;    and pharmaceutically acceptable salts thereof. The breakdown    products of such compounds, lactic acid and the amino acid, are both    well accepted physiologically.

The compounds of the invention can form salts which form an additionalaspect of the invention. Appropriate pharmaceutically acceptable saltsof the compounds of Formula I include salts of organic acids, especiallycarboxylic acids, including but not limited to acetate,trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate,malate, pantothenate, isethionate, adipate, alginate, aspartate,benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate,glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate,palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate,tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate,organic sulphonic acids such as methanesulphonate, ethanesulphonate,2-hydroxyethane sulphonate, camphorsulphonate, 2-napthalenesulphonate,benzeuesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate;and inorganic acids such as hydrochloride, hydrobromide, hydroiodide,sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoricand sulphonic acids. The compounds of Formula I may in some cases beisolated as the hydrate.

The term “N-protecting group” or “N-protected” as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undesirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in Greene, “Protective Groups in Organic Synthesis” (JohnWiley & Sons, New York, 1981), which is hereby incorporated byreference. N-protecting groups include acyl groups such as formyl,acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl,2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl,o-nitrophenoxyacetyl, α-chlorobutyl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl, and the like, carbamate forminggroups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycabonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymetyl andthe like; and silyl groups such as trimethylsilyl and the like. FavouredN-protecting groups include formyl, acetyl, allyl, F-moc, benzoyl,pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC)and benzyloxycarbonyl (Cbz).

Hydroxy and/or carboxy protecting groups are also extensively reviewedin Greene ibid and include ethers such as methyl, substituted methylethers such as methoxymethyl, methylthiomethyl, benzyloxymetyl,t-butoxymethyl, 2-methoxyethoxymethyl and the like, silyl ethers such astrimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS) tibenzylsilyl,triphenylsilyl, t-butyldiphenylsilyl triisopropyl silyl and the like,substituted ethyl ethers such as 1-ethoxymethyl,1-methyl-1-methoxyethyl, t-butyl allyl, benzyl, p-methoxybenzyl,dipehenylmethyl, triphenylmethyl and the like, aralkyl groups such astrityl, and pixyl (9-hydroxy-9-phenylxanthene derivatives, especiallythe chloride). Ester hydroxy protecting groups include esters such asformate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate,pivaloate, adamantoate, mesitoate, benzoate and the like. Carbonatehydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyland the like.

In keeping with the usual practice with retroviral and HBV inhibitors itis advantageous to co-administer one to three or more additionalantivirals, such as AZT, ddI, ddC, d4T, 3TC, H2G, foscarnet, ritonavir,indinavir, saquinavir, nevirapine, delaviridine, Vertex VX 478 orAgouron AG1343 and the like in the case of HIV or lamivudine,interferon, famciclovir etc in the case of HBV. Such additionalantivirals will normally be administered at dosages relative to eachother which broadly reflect their respective therapeutic values. Molarratios of 100:1 to 1:100, especially 25:1 to 1:25, relative to thecompound or salt of formula I will often be convenient. Administrationof additional antivirals is generally less common with those antiviralnucleosides intended for treating herpes infections.

While it is possible for the active agent to be administered alone, itis preferable to present it as part of a pharmaceutical formulation.Such a formulation will comprise the above defined active agent togetherwith one or more acceptable carriers/excipients and optionally othertherapeutic ingredients. The carrier(s) must be acceptable in the senseof being compatible with the other ingredients of the formulation andnot deleterious to the recipient.

The formulations include those suitable for rectal, nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous and intradermal)administration, but preferably the formulation is an orally administeredformulation. The formulations may conveniently be presented in unitdosage form, e.g. tablets and sustained release capsules, and may beprepared by any methods well known in the art of pharmacy.

Such methods include the step of bringing into association the abovedefined active agent with the carrier. In general, the formulations areprepared by uniformly and intimately bringing into association theactive agent with liquid carriers or finely divided solid carriers orboth, and then if necessary shaping the product. The invention extendsto methods for preparing a pharmaceutical composition comprisingbringing a compound of Formula I or its pharmaceutically acceptable saltin conjunction or association with a pharmaceutically acceptable carrieror vehicle. If the manufacture of pharmaceutical formulations involvesintimate mixing of pharmaceutical excipients and the active ingredientin salt form, then it is often preferred to use excipients which arenon-basic in nature, i.e. either acidic or neutral.

Formulations for oral administration in the present invention may bepresented as discrete units such as capsules, cachets or tablets eachcontaining a predetermined amount of the active agent; as a powder orgranules; as a solution or a suspension of the active agent in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water in oil liquid emulsion and as a bolus etc.

With regard to compositions for oral administration (e.g. tablets andcapsules), the term suitable carrier includes vehicles such as commonexcipients e.g. binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose,ethylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers,for example corn starch, gelatin, lactose, sucrose, microcrystallinecellulose, kaolin, mannitol, dicalciun phosphate, sodium chloride andalginic acid; and lubricants such as magnesium stearate, sodium stearateand other metallic stearates, glycerol stearate stearic acid, siliconefluid, talc waxes, oils and colloidal silica. Flavouring agents such aspeppermint, oil of wintergreen, cherry flavoring or the like can also beused. It may be desirable to add a colouring agent to make the dosageform readily identifiable. Tablets may also be coated by methods wellknown in the art.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active agent in a free flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, preservative, surface-active or dispersingagent. Moulded tablets may be made by moulding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.The tablets may be optionally be coated or scored and may be formulatedso as to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include lozengescomprising the active agent in a flavoured base, usually sucrose andacacia or tragacanth; pastilles comprising the active agent in an inertbase such as gelatin and glycerin, or sucrose and acacia; andmouthwashes comprising the active agent in a suitable liquid carrier.

A still further aspect of the invention provides a method for thepreparation of a compound of Formula I or Ic comprising the acylation ofthe nucleoside, represented here by FLG, Formula V, typically at the 5′hydroxy group:

in which R₁(R₂)L₁X represents an activated acid, such as the carboxylicderivatives of Formula IIa or IIb, where R₁, R₂, and L₁ are as definedabove or protected derivatives thereof. Alternatively the activated acidmay comprise a compound of the formula R₁(R₂)glycerol-D-X, where R₁, R₂and D are as defined in formula IIc or an activated Rz-O-Alk-C(═O)Xderivative in the case of compounds of formula Ia In the latter casesthe linkers may be built up sequentially by first esterifying a suitablyprotected D or ω-hydroxy carboxylic acid to the nucleoside, deprotectingthe terminal carboxy or hydroxy function and esterifying the suitablyprotected glycerol or Rz moiety thereon.

The activated derivative used in the acylation may comprise e.g, theacid halide, acid anhydride, activated acid ester or the acid in thepresence of coupling reagent, for example dicyclohexylcarbodiimide.Representative activated acid derivatives include the acid chloride,anhydrides derived from alkoxycarbonyl halides such asisobutyloxycarbonylchloride and the like, N-hydroxysuccinamide derivedesters, N-hydroxyphthalimide derived esters,N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters,2,4,5-trichlorophenol derived esters and the like. Further activatedacids include those where X in the formula RX represents an OR′ moietywhere R is R₂ as defined herein, and R′ is, for example COCH₃, COCH₂CH₃or COCF₃ or where X is benzotriazole.

Corresponding methodology will be applicable when the invention isapplied to other monohydroxylated nucleosides, that is the activatedderivative is correspondingly esterified to the free 5′ hydroxy (orequivalent) of monohydric nucleosides such as acyclovir, ddI, FTC,lamivudine, 1592U89, DAPD, F-ddA and the like.

The intermediates used in the above methods themselves define novelcompounds, especially those of the formula: IIc′

where A, A′ and Alk are as defined above (A and A′ being optionallyprotected with conventional protecting groups) and X represents the freeacid or an activated acid as illustrated above.

Corresponding compounds to those of formula IIc′ include;

-   malonic acid 2,3-bis-(L-valyloxy)-propyl ester,-   malonic acid 2,3-bis-(N-CBZ-L-valyloxy)-propyl ester,-   malonic acid 2,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,-   malonic acid 2,3-bis-(N-Boc-L-valyloxy)-propyl ester,-   malonic acid 2,3-bis-(L-isoleucyloxy)-propyl ester,-   malonic acid 2,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,-   malonic acid 2,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,-   malonic acid 2,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,-   succinic acid 2,3-bis-(L-valyloxy)-propyl ester,-   succinic acid 2,3bis-(N-CBZ-L-valyloxy)-propyl ester,-   succinic acid 2,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,-   succinic acid 2,3-bis-(N-Boc-L-valyloxy)-propyl ester,-   succinic acid 2,3-bis-(L-isoleucyloxy)-propyl ester,-   succinic acid 2,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,-   succinic acid 2,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,-   succinic acid 2,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,-   glutaric acid 2,3-bis-(L-valyloxy)-propyl ester,-   glutaric acid 2,3-bis-(N-CBZ-L-valyloxy)-propyl ester,-   glutaric acid 2,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,-   glutaric acid 2,3-bis-(N-Boc-L-valyloxy)-propyl ester,-   glutaric acid 2,3-bis-(L-isoleucyloxy)-propyl ester,-   glutaric acid 2,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,-   glutaric acid 2,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,-   glutaric acid 2,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,    and the corresponding acid halides, in particular the chloride, acid    anhydrides and diesters of each of the above, for instance-   succinic acid 2,3-bis-(N-CBZ-L-valyloxy)-propyl ester,    4-methoxybenzyl ester-   succinic acid 2,3-bis-(N-CBZ-L-valyloxy)-propyl ester,    1,1-dimethylethyl ester, etc.

A preferred group of compounds in Formula IIc′ include

-   malonic acid 1,3-bis-(L-valyloxy)-propyl ester,-   malonic acid 1,3-bis-(N-CBZ-L-valyloxy)-propyl ester,-   malonic acid 1,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,-   malonic acid 1,3-bis-(N-Boc-L-valyloxy)-propyl ester,-   malonic acid 1,3-bis-(L-isoleucyloxy)-propyl ester,-   malonic acid 1,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,-   malonic acid 1,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,-   malonic acid 1,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,-   succinic acid 1,3-bis-(L-valyloxy)-propyl ester,-   succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-propyl ester,-   succinic acid 1,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,-   succinic acid 1,3-bis-(N-Boc-L-valyloxy)-propyl ester,-   succinic acid 1,3-bis-(L-isoleucyloxy)-propyl ester,-   succinic acid 1,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,-   succinic acid 1,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,-   succinic acid 1,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,-   glutaric acid 1,3-bis-(L-valyloxy)-propyl ester,-   glutaric acid 1,3-bis-(N-CBZ-L-valyloxy)-propyl ester,-   glutaric acid 1,3-bis-(N-Fmoc-L-valyloxy)-propyl ester,-   glutaric acid 1,3-bis-(N-Boc-L-valyloxy)-propyl ester,-   glutaric acid 1,3-bis-(L-isoleucyloxy)-propyl ester,-   glutaric acid 1,3-bis-(N-CBZ-L-isoleucyloxy)-propyl ester,-   glutaric acid 1,3-bis-(N-Fmoc-L-isoleucyloxy)-propyl ester,-   glutaric acid 1,3-bis-(N-Boc-L-isoleucyloxy)-propyl ester,    and the corresponding acid halides, in particular the chloride, acid    anhydrides and diesters of each of the above, for instance-   succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-propyl ester,    4-methoxybenzyl ester-   succinic acid 13-bis-(N-CBZ-L-valyloxy)-propyl ester,    1,1-dimethylethyl ester, etc.

A further preferred group of intermediates comprise those of the formulaIIa′:

where R_(x), Alk, m, n and T are as described above, A and A′ representacyl residues of L′-aliphatic amino acids (N-protected as necessary)esterfied to hydroxy functions on the linker or one of A and A′ is theacyl residue and the other is a free hydroxy group, and X represents thefree acid or an activated acid as illustrated above. Preferably A and A′are the same amino acid residue.

Other novel intermediates include the free or activated acid precursorsof compounds of the formula Ia such as:

-   3-N-Boc-L-valyloxypropanoic acid, 3-N-Fmoc-L-valyloxypropanoic acid,    3-N-CBZ-L-valyloxypropanoic acid, 3-N-Boc-L-isoleucyloxypropanoic    acid, 3-N-Fmoc-L-isoleucyloxypropanoic acid,    3-N-CBZ-L-isoleucyloxypropanoic acid, 4-N-Boc-L-valyloxybutyric    acid, 4-N-Fmoc-L-valyloxybutyric acid, 4-N-CBZ-L-valyloxybutyric    acid, 4N-Boc-L-isoleucyloxybutyric acid,    4-N-Fmoc-L-isoleucyloxybutyric acid, 4-N-CBZ-L-isoleucyloxybutyric    acid and the like;    and the activated derivatives, such as the acid halides

Further novel intermediates include precursors of compounds of theformula IIe and IIf above, especially those derived from “natural”configurations such as L-malic and L-tartaric acid; for instance:

-   3-ethoxycarbonyl-2-valyloxy-propionic acid-   3-ethoxycarbonyl-2-isoleucyloxy-propionic acid-   4-ethoxycarbonyl-2,3-bis-valyloxy-butyric acid-   4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyric acid-   3-t-butoxycarbonyl-2-valyloxy-propionic acid-   3-t-butoxycarbonyl-2-isoleucyloxy-propionic acid-   4-t-butoxycarbonyl-2,3-bis-valyloxy-butyric acid-   4-t-butoxycarbonyl-2,3-bis-isoleucyloxy-butyric acid-   3-benzyloxycarbonyl-2-valyloxy-propionic acid-   3-benzyloxycarbonyl-2-isoleucyloxy-propionic acid-   4-benzyloxycarbonyl-2,3-bis-valyloxy-butyric acid-   4-benzyloxycarbonyl-2,3-bis-isoleucyloxy-butyric acid, and the like;    the corresponding compounds wherein the amino acid is N-protected,    particularly with a protecting group allowing selective deprotection    of the N-protective group without removal of the carboxy protecting    group; and the corresponding activated derivatives such as the acid    halides.

Still further novel intermediates include precursors corresponding tostructure IId, such as;

-   2-(L-valyloxy)propanoic acid, 2-(N-Boc-L-valyloxy)propanoic acid,    2-(N-Fmoc-L-valyloxy)propanoic acid, 2-(N-CBZ-L-valyloxy)propanoic    acid, 2-(L-isoleucyloxy)propanoic acid,    2-N-Boc-L-isoleucyloxy)propanoic acid,    N-(Fmoc-L-isoleucyloxy)propanoic acid,    N-(CBZ-L-isoleucyloxy)propanoic acid,-   2-(L-valyloxy)butyric acid, 2-(N-Boc-L-valyloxy)butyric acid,    2-(N-Fmoc-L-valyloxy)butyric acid, 2-(N-CBZ-L-valyloxy)butyric acid,    2-(L-isoleucyloxy)butyric acid, 2-(N-Boc-L-isoleucyloxy)butyric    acid, N-(Fmoc-L-isoleucyloxy)butyric acid,    N-(CBZ-L-isoleucyloxy)butyric acid, and the like;    and activated derivatives therof, such as the acid halides.

Preparation of 3′ fluoronucleosides such as those of formula V has beenextensively reviewed by Herdiwijn et al. in Nucleosides and Nucleotides8 (1) 65-96 (1989), which is hereby incorporated by reference. Thepreparation of other monohydric nucleosides such as acyclovir, ddI(didanosine), ddC (zalcitabine), d4T (stavudine), FTC, lamivudine (3TC),1592U89(4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol),AZT (zidovudine), DAPD (D-2,6-diaminopurine dioxolane), F-ddA and thelike are well known and extensively described in the literature.

The reactive derivatives of the R₁(R₂)L₁L₂X group may be pre-formed orgenerated in situ by the use of reagents such asdicyclohexylcarbodiimide (DCC) or O-(1H-benzotriazol-1-yl)N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU). When an acidhalide, such as the acid chloride is used, a tertiary amine catalyst,such as triethylamine, N,N′-dimethylaniline, pyridine ordimethylaminopyridine may be added to the reaction mixture to bind theliberated hydrohalic acid.

The reactions are preferably carried out in an unreactive solvent suchas N,N-dimethylformamide, tetahydrofuran, dioxane, acetonitrile or ahalogenatated hydrocarbon, such as dichloromethane. If desired, any ofthe above mentioned tertiary amine catalysts may be used as solvent,taking care that a suitable excess is present. The reaction temperaturecan typically be varied between 0° C. and 60° C., but will preferably bekept between 5° and 50° C. After a period of 1 to 60 hours the reactionwill usually be essentially complete. The progress of the reaction canbe followed using thin layer chromatography (TLC) and appropriatesolvent systems. In general, when the reaction is completed asdetermined by TLC, the product is extracted with an organic solvent andpurified by chromatography and/or recrystallisation from an appropriatesolvent system.

By-products where acylation has taken place on the nucleoside base canbe separated by chromatography, but such misacylation can be minimizedby controlled reaction conditions. These controlled conditions can beachieved, for example, by manipulating the reagent concentrations orrate of addition, especially of the acylating agent, by lowering thetemperature or by the choice of solvent. The reaction can be followed byTLC to monitor the controlled conditions. It may be convenient toprotect the 6-oxo group on the base and especially the 2 amino withconventional protecting groups to forestall misacylation.

Compounds of Formula IV in which R₃ is hydrogen may be prepared by6-activating the correponding guanine compound of Formula I (wherein theexposed amino function of the amino acid residue of R₂ is optionallyprotected with conventional N-protecting groups) with an activatinggroup such as halo. The thus activated 6-purine is subsequently reducedto purine, for instance with a palladium or nickel catalyst anddeprotected to the desired compound of Formula IV or Formula V.

Compounds wherein R₃ is an R₁ or other ester may be prepared byconventional esterification (analogous to the esterification describedabove) of the corresponding hydroxy compound of Formula I or Formula V,optionally after conventional N-protecting the exposed amine function ofthe amino acid residue of R₂ and/or R₃. Compounds wherein R₃ is an ethermay be prepared analogously to the process disclosed in theabovementioned WO 93 13778, again in conjunction with optionalN-protection of exposed amine groups. Compounds wherein R₃ is an azidecan be prepared as described in WO 97 09052.

Intermediates of the formula IId are conveniently prepared by acylationof a carboxy-protected hydroxy alkanoic acid, typically a2-hydroxy-1-alkanoic acid, with the appropriate activated andN-protected R₂ derivative, such as N-CBZ valyl or isoleucyl inconjunction with a conventional coupling reagent such as DMAP/DCC orwith the amino acid halide. The carboxy protecting group is thenremoved, for instance by acid hydrolysis and the resulting intermediateis activated as described above or the free acid is unsed in conjunctionwith a coupling reagent to esterify the the nucleoside underconventional esterification conditions.

Compounds within the scope of the invention are also convenientlyprepared by the methodology in the immediately preceding paragraph,namely esterification of a carboxy protected α-hydroxy, ω-carboxy acid,such as glycollic acid, lactic acid, hydroxybutyric acid etc with theappropriate N-protected R₂ derivative, either as the free acid inconjunction with a coupling agent or activated, for instance to thecorresponding acid halide. The carboxy protecting group is removed andthe resulting intermediate esterified with the nucleoside with themethodology described above.

Compounds comprising a structure of the formula IIe or IIf are preparedby carboxy protecting the terminal carboxy groups of the respectivedicarboxylic acid, such as L-tartaric acid or L-malic acid, withconventional carboxy protecting groups such as benzyl. The free hydroxygroup(s) are then esterified with conventional esterificationtechniques, such as DMAP & DCC in DMF with the appropriate N-protectedR₂ amino acid, such as N-Boc-L-valyl or N-Boc-L-isoleucyl. The benzylcarboxy protecting groups are removed and the resulting product isesterfied to the 5′-hydroxy function of a monohydric nucleoside, usingconventional conditions, such as those in the accompanying Examples.Finally, the free carboxy function is esterified with an R₁ group or,more preferbably a conventional pharmaceutically acceptable ester, suchas the ethyl ester.

Compounds comprising a phosphorylated moiety III may be prepared byreacting 2′,3′-dideoxy-3′-fluoroguanine-5monophosphate with a compoundof Formula VIa

where Ha is halo, such as chloro, iodo or bromo, in analagous conditionsto those described in U.S. Pat. No. 4,337,201, U.S. Pat. No. 5,227,506,WO 94/13682 & WO 94/13324, Starret et al J Med Chem 37 1857-1864 (1994)and Iyer et al Tetrahedron Lett 30 7141-7144 (1989) which areincorporated herein by reference. The monophosphate can be prepared byconventional phosphorylation of FLG, as described, for instance, inHerdwyn et al ibid. Corresponding methodology will apply to themonophosphates of other monohydric nucleosides.

Compounds comprising an optional linker L₂ may also be prepared by a twostage process. In particular a compound of the formulaClC(═O)OC(R₄)(R₄′)Cl can be reacted with the 5′-hydroxy of FLG(optionally protected on the base with conventional protecting groups)as is known in the cephalosporin art. The resultingFLG-5′—O—C(═O)OC(R₄)(R₄′)chloride is then reacted with an R₁ and R₂bearing trifunctional linker wherein the third function comprises acarboxyl function, such as the potassium salt.

It will be appreciated that trifunctional L₁ groups of formula IIawherein and n and m are 1 and Alk is absent can be prepared fromglycerol by regioselective esterfication as depicted below in scheme 1by reference to a stearoyl/L-valyl combination. In short R₁ and R₂ areregioselectively esterfied to positions 1 and 3 of the glycerol andposition 2 is then converted to the appropriate -T-C(═O)-group, which isthen esterified to the 5′-position of the fluoronucleoside or to acooperating function on L₂ (not depicted). Alternatively the hydroxy atposition 2 of the glycerol derivative can be esterified with an L₂ groupcontaining a cooperating carbonyl function on its left hand end.

L₁ groups of formula IIa wherein m is 1, n is 0 and Alk is methylene canalso be prepared from glycerol by regioselectively esterifying R₁ and R₂to positions 1 and 2 of the glycerol, as also depicted below in scheme1, followed by conversion of the hydroxy at position 3 to theappropriate -T-C(═O)-group. The leftmost series of reactions on Scheme 1shows the situation where R₁ is esterified to position 1 of the glyceroland R₂ is esterified to position 2. The corresponding arrangement whereR₃ is esterified to position 2 and R₂ to position 1 can be achieved byfirst treating the glycerol with CBz-L-valine/DCC/DMAP/DMF and thenprotecting the 3 position with pixyl chloride prior to esterifying thefatty acid of R₁ to position 2 of the glycerol, deprotecting andconverting the 3 position as necessary.

Although Scheme 1 has been illustrated by reference to a combinationwherein R₁ is stearoyl and R₂ is L-valyl, it will be appreciated thatthis basic scheme will also be applicable to other amino acids, wherepresent other fatty acids, or using conventional protection groups, tocombinations of R₂ as an amino acid derivative and R₁ as hydroxy.Linkers where T comprises an —NH— group can be prepared by analogousregioselective esterification followed by conversion of the freehydroxyl to amine, reduction to azide and reaction with phosgene to formthe corresponding chlorocarbamate.

A variation of scheme I allowing the preparation of linkers of theformula IIc. In this variation, the phosgene step shown above isreplaced by reaction with an activated dicarboxylic acid, such assuccinic anhydride. This results in a glycerol triester (comprising the(optionally protected) R₁ ester, the protected R₂ ester and the ester ofthe dicarboxylic acid) and the free carboxy on the dicarboxylic acid isthen activated and esterified to the nucleoside in a conventionalfashion. Alternatively linkers of formula IIc can be built up in situ onthe nucleoside. In this variant, the dicarboxylic acid is esterified toa suitably protected glycerol derivative. This succinyl monoester isthen esterified to the 5′-hydroxy function of the nucleoside in aconventional manner. Finally one or both of the protecting groups on theglycerol moiety is replaced with the L-amino acid ester, and, ifpresent, the remaining protecting group is replaced with a fatty acidester or removed to leave a free hydroxy group This is depicted inScheme IA which illustrates an example wherein the nucleoside inacyclovir (FLG shown in shadow), the dicarboxylic acid is succinyl andR₁ and R₂ are both CBZ-protected valyl, but will, of course beapplicable to other variations of Formula Ic. In each case couplingconditions means standard esterification conditions such as couplingreagents DMAP, DCC etc or alternatively conversion of the relevantcarboxy function to an activated derivative such as the acid chloride orthe activated succinic moiety can also comprise the anhydride.

In a variation of Scheme IA, the succinic anhydride is reacted directlywith the nucleoside, thus avoiding the first protection and deprotectionsteps. A further alternative is to regioselectively esterify theglycerol moiety with the N-protected amino acid moiety(ies), generallyin conjunction with protection of the hydroxy function intended forcoupling to the nucleoside, followed by deprotection of that hydroxy andcoupling to the nucleoside.

Linkers where m and n are 1, Alk is alkylene or alkenylene and T is abond can be prepared as shown in Scheme II above. Other permutations ofm, n, Alk and the various functions in the trifunctional linker group L₁of formula IIa can be prepared analagously to the above with thecorresponding starter materials, such as 1,2,4-trihydroxybutane (CAregistry number 3968-00-6), 3,4-dihydroxybutanoic acid (1518-61-2 &22329-74-4), (S)-3,4-dihydroxybutanoic acid (51267-44-8),(R)-3,4-dihydroxybutanoic acid (158800-76-1), 1,2,5-pentanetriol(51064-73-4 & 14697-46-2), (S)-1,2,5-pentanetriol (13942-73-9),(R)-1,2,5-pentanetriol (171335-70-9), 4,5-dihydroxypentanoic acid(66679-29-6 & 129725-14-0), 1,3,5-pentanetriol (4328-94-3) and3-(2-hydroxyethyl)-1,5-pentanediol (53378-75-9). The preparation of eachof these starting materials is described in the references to therespective registry number. Ohsawa et al in Chem Pharm Bull 41 (11)1906-1909 (1993) and Terao et al Chem. Pharm. Bull. 39(3) 823-825 (1991)describe the control of the sterochemistry of trifunctional linkergroups with lipase P.

The amino acid derivative of R₂ and, if present, R₁ can alternatively beesterified to the linker group with the2-oxa-4-aza-cycloalkane-1,3-dione methodology described in internationalpatent application no. WO 94/29311, the contents of which are herebyincorporated by reference.

Linking of the carboxy function of R₁ and/or R₂ to an amine group on thelinker derivative proceeds by conventional peptide chemistry, generallyin conjunction with protection of the α-amine with conventionalN-protecting groups. Formation of an amide bond between a carboxylfunction on the linker and the α-amine group of R₂ also proceeds byconventional peptide chemistry, generally in conjunction with protectionof the α-carboxy function. Esterification of R₁ as a fatty alcohol to acarboxy function on the linker proceeds analogously, but conversely, tothe above esterifiation of R₁ as a fatty acid.

The above description has centred around monohydric nucleosidesderivatised with a linker group which in turn is derivatised with anester residue of an aliphatic amino acid, and, optionally, the acylresidue of a fatty acid.

In a further aspect of the invention, however, said linker group andderivatised aliphatic amino acid ester, but this time without theoptional fatty ester, can be applied to a broader range of drugs. Thusthe invention further provides compounds of the formula D-L*-R₂ where R₂is the amide or ester residue of an aliphatic amino acid, D is a drugresidue bearing an accesible function such as an amine, hydroxy,carboxy, phosphonate, phosphinate or phosphoryl function and L is an atleast bifunctional linker comprising a first function bound to saidaccessible function spaced from a second function forming an amide oracyl bond with the aliphatic amino acid.

The prodrugs of this aspect of the invention are distinct from thosedescribed in WO98/21233 in that the latter comprise an obligatory fattyacid ester.

Drug residue as used in its conventional significance, that is implyingthat during linkage a hydrogen or hydroxy has been eliminated from anaccessible amino, phosphoryl, phosphinyl, phosphonyl, carboxy or hydroxyfunction on the Drug. The amine function on the Drug can be a primaryamine (—NH₂) or a secondary amine (—NH—). The amino acid of R₂ may beoptionally N-protected in those configurations where it possesses a freeamine function.

The expression difunctional in the context of the linker group L meansthat the linker has at least one hydroxy or amine function available foresterification or amide bonding with R₂, or a carboxyl functionavailable for amide bonding with the free α-amine function of R₂. Spacedtherefrom on the difunctional linker is a further functional group forlinkage to a cooperating function on the Drug such as hydroxy, carboxy,phosphonyl, phosphoryl, phosphinyl and the like.

The linker may in fact be trifunctional, that is the linker has at leastthree functions including two independently selected from hydroxy, amineor carboxy, the amine and hydroxy function(s) being available foresterification/amide bonding with the carboxyl functions of a pair ofR₂, or the carboxy function(s) on the linker being available for amidebonding with the free α-amine function of R₂. Thesehydroxy/amine/carboxy functions are spaced from a further functionalgroup for linkage with a cooperating function on the drug, such ashydroxy, carboxy, phosphonyl, phosphoryl, phosphinyl, amine etc. Othertrifunctional linker groups may comprise a first hydroxy, amine orcarboxy function cooperating with R₂, a function cooperating with thedrug and a further functional group either underivatised such ashydroxy, carboxy, amine etc or alternatively protected with conventionalpharmaceutically acceptable protecting groups.

The invention further provides pharmaceutical compositions comprisingthe compounds of the present broader aspect of the invention andpharmaceutically acceptable carriers or diluents therefor. Additionalaspects of the invention provide methods of medical treatment orprophylaxis comprising the administration of a compound of the inventionto a human or animal suffering from or prone to the ailment to which therespective Drug is applicable.

By the use of the invention the pharmacokinetics of a broad range oforally administered drugs are enhanced, for instance by improvingabsolute bioavailability or by providing a more even release of themother compound or by providing for a reduced interpersonal spread inpharmacokinetic performance. However the compounds of the invention arenot limited to those based on orally administered drugs as the prodrugsof the invention, when parenterally administered, provide enhancedpharmacokinetic performance, for instance by improving solubility, whilestill allowing for efficient release of the mother compound.

Linker as used in this second aspect of the invention specificallyembraces each and every linker described above in relation to themonohydric nucleoside aspect of the invention (to the extent that theseomit a fatty acid ester), including the structures >L₁L₂ and structuresof the formulae IIa, IIb, IIc, IId, IIe, IIf, IIIa, IIIb, IIIc,(optionally protected) tartaric and malic acid linkers, and linkersdepicted in formulae I, Ia, Ic, Ic′, Id, If and Ig. However it will beapparent that these linker structures are of wider applicability thanthe monohydric nucleosides there described.

Convenient linker groups, for instance when the Drug comprises an amineor hydroxy function, include those of the Formulae IIaa or II′aa

where A and A′ are independently an ester linkage between an hydroxy onthe linker and the carboxy on R₂ (or a pair of R₂), or an amide linkagebetween an amine on the linker and a carboxy on R₂ or a pair of R₂;

-   -   Q is a structure:    -   or Q is a monocyclic, saturated or unsaturated carbo- or        heterocycle with 4, 5 or 6 ring atoms;    -   Alk is absent, C₁-C₄ akylene or C₂-C₄ alkenylene;    -   T is a bond, —O— or —N(R₄)—,    -   V is a bond or a structure of the formula IIbb or IIcc:    -   R₄ and R₄′ are independently hydrogen or C₁-C₃ alkyl; and    -   m and n are independently 0, 1 or 2;

In Formulae IIa-IIe, Q as a ring is preferably an aromatic group such aspyridine, furyl, imidazol etc or especially phenyl, such as aromaticmoieties wherein the arm(s) bearing the or each R₂ group arerespectively para and meta or both meta to the remainder of the linker.

Particularly convenient structures when the drug comprises an hydroxyfunction include the corresponding structures to:formulae IIc*, that is

formula II e*, that is

formula II f*, that is

Formula Id*, that is

Where the Drug comprises a carboxyl function, the linker may comprise astructure of the formulae VIII or VIII′:

where A, A′, Q, Alk, m, and n are as defined for Formula IIaa & II′aa.

Preferably, however, when the Drug comprises a carboxy function, the di-or trifunctional linker group L is a structure of Formulae IIdd or II′dd(that is a compound of Formulae IIaa or II′aa, wherein T is O and V is astructure of the formula IIbb):

In structure IIdd, R₄′ is preferably hydrogen and R₄ is ethyl, phenyl,and especially methyl or hydrogen or R₄ and R₄, together defineisopropyl

Where the Drug comprises a phosphoryl, phosphinyl or phosphonylfunction, the di- or trifunctional linker group L may comprise astructure of the formula IIaa or lI′aa, especially those of the formulaIIee or II′ee:

where T is a bond, —NH— or —O— and Q and A are as defined aboveincluding the cyclic Q structures such as cycloalkyl, phenyl andheterocycles such as furyl, pyridyl etc. In structures IIee and IIee,R₄′is preferably hydrogen and R₄ is methyl, ethyl, phenyl and especiallyhydrogen or R₄ and R₄, define isopropyl.Preferably, however, where the Drug comprises a phosphonyl, phosphinylor phosphoryl function, the difunctional linker comprises a structure ofthe formula II″b:

where T is a bond, —O— or —NH—, R_(4l) R_(4r) and R_(4lr)′ and R_(4r)′are independently H or C₁-C₃ alkyl and A is as defined above (or whereinA is a further difunctional linker to which one or more R₂ depends asdescribed above). Examples of structures belonging to the latterpossibility for A include those of Formula Va and Vb:

where T, q, R₂, R_(4l) R_(4l)′ R_(4r) and R_(4r)′ are as defined above.Although formulae Va and Vb depict the dicarboxylate moiety asunbranched, it will be apparent that a wide variety of dicarboxylateswill be suitable here, including branched and/or unsaturated and/orsubstituted dicarboxylic acid derivatives or various lengths, asdescribed in more detail above.

Amongst the preferred configurations for formulae II′b, Va and Vb, arethose wherein T is absent.

Convenient values for the rightmost R₄ and R_(4′) are hydrogen and forthe left most R₄ and R_(4′) both methyl. Other preferred embodimentscomprise structures of the formulae II″b, Va or Vb wherein the rightmostR₄ is H and the rightmost R₄ is isopropyl, cycloC₁₋₆alkyl, phenyl orbenzyl.

Convenient values of the rightmost q and leftmost q are as follows:

-   zero:1-   zero:2,-   zero:3-   1:1-   1:zero-   2:2-   3:zero-   3:1.

Still further preferred embodiments comprise structures of the formulaII″b, Va or Vb wherein T is —NH— or —O—.

In drugs comprising multiple phosphoryl/phosphonate/phosphinatefunctions, it is generally advantageous that an hydroxy group on eachphosphorous moiety is esterified with a structure of Formula II′e orII″b etc. Regioselective protecting groups which bridge the phosphategroups of bis phosphonates and thus assist mono and diacylation includeSi compounds such as dichlorotetraisopropyldisosiloxane.

Methodology for the derivatisation of phosphorous containing compoundswith acyloxyalkyl groups and which can be used analogously for thecoupling of the difunctional and trifunctional linkers of the inventionis described in U.S. Pat. No. 5,227,506, WO 94/13682, WO 94/13324, WO98/04569 Starret et al J Med Chem 37 1857-1864 (1994) and Iyer et alTetrahedron Lett 30 7141-7144 (1989).

A further aspect of the invention comprises novel intermediates usefulin applying structures of the formulae II″b to a drug and having theformula N-1:

where A, q, R₄, R₄′ and T are as defined for formula II″b.

A particularly preferred group of compounds substantially within formulaN-1 are those of the formula N-2

where

-   R₂ is the acyl residue of an aliphatic amino acid,-   R_(3L) and R_(3L)′ are independently H, C₁₋₃ alkyl, C₃₋₆cycloalkyl,    C₁-₃alkyl-C₁C₆cycloalkyl phenyl or benzyl,-   R_(3R) and R_(3R)′ are independently H or C₁₋₃ alkyl-   qI is 0-3, qr is 0-3,-   T is a bond, —NR₃— or —O—-   R₃ is H or C₁₋₃alkyl;    “ring” is an optionally substituted aromatic or non-aromatic,    hetero-or carbocycle; and    halo is bromo, chloro or iodo.

Representative compounds within formula N-2 include:

-   2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid iodomethyl ester-   3,3-bis (N-CBz-L-valyloxymethyl)-propionic acid iodomethyl ester,-   2-(N-CBz-L-valyloxy)ethoxycarbonyloxymethyl iodide-   Iodomethyl 1,3-bis(N-benzyoxycarbonyl-L-valyloxy)-2-propyl    carbonate,-   Iodomethyl    2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionate,-   Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-DL-propionate.-   Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy)isobutyrate.-   Iodomethyl    2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate.-   Iodomethyl 2-O-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate-   Iodomethyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate.-   Iodomethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate-   2-(N-CBz-L-valyloxy)-ethyl iodomethyl carbonate-   4-(N-CBz-L-valyloxy) butyric acid iodomethyl ester-   Iodomethyl-3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate-   Iodomethyl-3-(N-benzyloxycarbonyl-L-valyloxy)-propionate-   1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1-iodoethyl    carbonate-   3-(N-benzyloxycarbonyl-L-valyloxy)-2,2-dimethylpropyl iodomethyl    carbonate-   Iodomethyl 3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate-   3-(N-CBZ-L-valyloxy)phenyl iodomethyl carbonate-   Iodomethyl 2-(N-CBZ-L-valyloxy)phenylacetate-   Iodomethyl 4-(N-CBZ-L-valyloxyxy)phenylacetate-   Iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl) benzoate-   Iodomethyl 4-(N-benzyloxycarbonyl-L-valyloxy)cyclohexanoate.-   Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl butyrate-   2-(N-(iodomethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane-   1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic    acid iodomethyl ester-   Iodomethyl 5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furoate-   Iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy)-benzoic acid-   2,2-dimethyl-3-(N-Boc-L-isoleucyloxy)propionic acid iodomethyl ester-   3,3-bis (N-CBz-L-isoleucyloxymethyl)-propionic acid iodomethyl    ester,-   2-(N-CBz-L-isoleucyloxy)ethoxycarbonyloxymethyl iodide-   Iodomethyl 1,3-bis(N-benzyloxycarbonyl-L-isoleucyloxy)-2-propyl    carbonate,-   Iodomethyl    2-methyl-2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)propionate,-   Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxy)-DL-propionate,-   Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxy)isobutyrate.-   Iodomethyl    2-(N-benzyloxycarbonyl-L-isoleucyloxy)-3-methyl-(S)-(+)-butyrate.-   Iodomethyl    2-(N-benzyloxycarbonyl-L-isoleucyloxy)-2-phenyl-DL-acetate-   Iodomethyl 4-(N-benzyloxycarbonyl-L-isoleucyloxy) benzoate.-   Iodomethyl 5-(N-CBz-L-isoleucyloxy)-2,2-dimethylvalerate-   2-(N-CBz-L-isoleucyloxy)-ethyl iodomethyl carbonate-   4-(N-CBz-L-isoleucyloxy) butyric acid iodomethyl ester-   Iodomethyl-3-(N-benzyloxycarbonyl-L-isoleuclyloxy)-benzoate-   Iodomethyl-3-(N-benzyloxycarbonyl-L-isoleucyloxy)-propionate-   1,3-bis(N-tert-butoxycarbonyl-L-isoleucyloxy)-2-propyl 1-iodoethyl    carbonate-   3-(N-benzyloxycarbonyl-L-isoleucyloxy)-2,2-dimethylpropyl iodomethyl    carbonate-   Iodomethyl 3,4-di-(N-CBz-L-isoleucyloxy)hydrocinnamate-   3-(N-CBz-L-isoleucyloxy)phenyl iodomethyl carbonate-   Iodomethyl 2-(N-CBz-L-isoleucyloxy)phenylacetate-   Iodomethyl 4-(N-CBz-L-isoleucyloxy)phenylacetate-   Iodomethyl 4-(2-N-benzyloxycarbonyl-L-isoleucyloxyethyl) benzoate-   Iodomethyl 4-(N-benzyloxycarbonyl-L-isoleucyloxy)cyclohexanoate,-   Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)-2-ethyl    butyrate,-   2-(N-(iodomethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-isoleucyloxy)-propane,-   1-(2-N-CBz-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic    acid iodomethyl ester-   iodomethyl 5-[(N-benzyloxycarbonyl-L-isoleucyloxy)methyl]-2-furoate-   iodomethyl 4-(2-N-benzyloxycarbonyl-L-isoleucyloxyethoxy)-benzoic    acid and the corresponding chloro analogues.

Further aspects of the invention include the use of intermediatecompounds, such as those of the formula N-1, N-2, IIc′, IIa′ VII, thefree or activated acid precursors of formula Ia, IIe, IId, IIf etc inthe preparation of a pharmaceutical prodrug.

The invention further provides pharmaceutical compositions comprisingthe compounds of the invention and pharmaceutically acceptable carriersor diluents therefor. Additional aspects of the invention providemethods of medical treatment or prophylaxis comprising theadministration of a compound of the invention to a human or animalsuffering from or prone to the ailment to which the respective Drug isapplicable.

Representative drugs having carboxyl functional groups include;

-   angiotensin-converting enzyme inhibitors such as alecapril,    captopril,    1-[4-carboxy-2-methyl-2R,4R-pentanoyl]-2,3-duhydro-2S-indole-2-carboxylic    acid, enalaprilic acid, lisinopril,    N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]glycine,    pivopril,    (2R,4R)-2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic    acid, (S) benzamido-4-oxo-6-phenylhexenoyl-2-carboxypyrrolidine,    [2S-1[R*(R*))]]2α,3αβ,7αβ]-1[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic    acid,    [3S-1[R*(R*))]],3R*]-2-[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolone    carboxylic acid and tiopronin;-   cephalosporin antibiotics such as cefaclor, cefadroxil, cefamandole,    cefatrizine, cefazedone, cefazuflur, cefazolin, cefbuperazone,    cefmenoxime, cefmetazole, cefodizime, cefonicid, cefoperazone,    ceforanide, cefotaxime, cefotefan, cefotiam, cefoxitin, cefpimizole,    cefpirome, cefroxadine, cefsulodin, cefpiramide, ceftazidime,    ceftezole, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile,    cephalexin, cephaloglycin, cephaloridine, cephalosporin, cephanone,    cephradine and latamoxef;-   penicillins such as amoxycillin, ampicillin, apalcillin,    azidocillin, azlocillin, benzylpencilln, carbenicillin, carfecillin,    carindacillin, cloxacillin, cyclacillin, dicloxacillin, epicillin,    flucloxacillin, hetacillin, methicillin, mezlocillin, nafcillin,    oxacillin, phenethicillin, piperazillin, sulbenicllin, temocillin    and ticarcillin;-   non-steroidal antiinflammatory agents such as acametacin,    alclofenac, alminoprofen, aspirin (acetylsalicylic acid),    4-biphenylacetic acid, bucloxic acid, carprofen, cinchofen,    cinmetacin, clometacin, clonixin, diclenofac, diflunisal, etodolac,    fenbufen, fenclofenac, fenclosic acid, fenoprofen, ferobufen,    flufenamic acid, flufenisal, flurbiprofin, fluprofen, flutiazin,    ibufenac, ibuprofen, indomethacin, indoprofen, ketoprofen,    ketorolac, lonazolac, loxoprofen, meclofenamic acid, mefenamic acid,    2-(8-methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)propionic    acid, naproxen, nifluminic acid, O-(carbamoylphenoxy)acetic acid,    oxoprozin, pirprofen, prodolic acid, salicylic acid,    salicylsalicylic acid, sulindac, suprofen, tiaproferic acid,    tolfenamic acid, tolmetin and zopemirac;-   prostaglandins such as ciprostene, 16-deoxy-16-hydroxy-16-vinyl    prostaglandin E₂, 16, 16-dimethylprostaglandin E₂, epoprostostenol,    meteneprost, nileprost, prostacyclin, prostaglandins E₁, E₂, or    F_(2a) and thromboxane A₂;-   quinolone antibiotics such as acrosoxacin, cinoxacin, ciprofloxacin,    enoxacin, flumequine, naladixic acid, norfloxacin, ofloxacin,    oxolinic acid, pefloxacin, pipemidic acid and piromidic acid.

Representative drugs containing amine groups include: acebutalol,albuterol, alprenolol, atenolol, bunolol, butopamine, butoxamine,

-   carbuterol, cartelolol, colterol, deterenol, dexpropanolol,    diacetolol, dobutamine, exaprolol, exprenolol, fenoterol, fenyripol,    labotolol, levobunolol, metolol, metaproterenol, metoprolol,    nadolol, pamatolol, penbutalol, pindolol, pirbuterol, practolol,    prenalterol, primidolol, prizidilol, procaterol, propanolol,    quinterenol, rimiterol, ritodrine, solotol, soterenol, sulfiniolol,    sulfinterol, sulictidil, tazaolol, terbutaline, timolol, tiprenolol,    tipridil, tolamolol, thiabendazole, albendazole, albutoin,    alinidine, alizapride, amiloride, aminorex, aprinocid, cambendazole,    cimetidine, clonidine, cyclobenzadole, etintidine, fenbendazole,    fenmetazole, flubendazole, fludorex, lobendazole, mebendazole,    metazoline, nocodazole, oxfendazole, oxibendazole, oxmetidine,    parbendazole, ranitidine, tetrahydrazoline, tiamenidine, tinazoline,    tiotidine, tolazoline, tramazoline, xylometazoline,    dimethoxyphenethylamine,    N-[3(R)-[2-piperidin-4-yl)ethyl]-2-piperidone-1-yl]acetyl-3(R)-methyl-β-alanine    adrenolone, aletamine, amidephrine, amphetamine, aspartame,    bamethan, betahistine, clorprenaline, chlortermine, dopamine,    ephrinephrine etryptamine, fenfluramine, methyldopamine,    norepinephrine, tocainide enviroxime, nifedipine, nimodipine,    triamterene, norfloxacin and similar compounds such as pipedemic    acid,    1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-napthyridine-3-carboxylic    acid,    1-cyclopropyl-6-fluoro-1,4dihydro-4-oxo-7-(piperazinyl)-3-quinolinecarboxylic    acid.

A favoured amine drug,[[3(R)-2-piperidin-4-ylethyl)-2-oxopiperidinyl]acetyl]-3(R)-methyl-β-alanine(also known as L-734,217) has the formula:

A further preferred amino drug are the bicyclam anti HIV agents, such asAMD 3100:

Representative drugs containing hydroxy groups include:

-   steroidal hormones such as allylestrenol, cingestol,    dehydroepiandrosteron, dienostrol, diethylstilbestrol,    dimethisteron, ethyneron, ethynodiol, estradiol, estron, ethinyl    estradiol, ethisteron, lynestrenol, mestranol, methyl testosterone,    norethindron, norgestel, norvinsteron, oxogeston, quinestrol,    testosteron and tigestol;-   tranquilizers such as dofexazepam, hydroxyzin, lorazepam and    oxazepam;-   neuroleptics such as acetophenazine, carphenazine, fluphenazine,    perphenyzine and piperaetazine;-   cytostatics such as aclarubicin, daunorubicin,    dihydro-5-azacytidine, doxorubicin, epirubicin, estramustin,    etoposide, 7-hydroxychlorpromazin, neplanocin A, pentostatin,    podophyllotoxin, vinblastin, vincristin, vindesin;-   hormones and hormone antagonists such as buserilin, gonadoliberin,    icatibrant and leuprorelin acetate;-   antihistamines such as terphenadine;-   analgesics such as diflunisal, naproxol, paracetamol, salicylamide    and salicyclic acid;-   antibiotics such as azidamphenicol, cefamandol, chloramphenicol,    clavulanic acid, clindamycin, comptothecin, demeclocyclin,    doxycyclin, imipenem, latamoxef, novobiocin, oleandomycin,    oxytetracyclin, tetracyclin and thiamenicol;-   prostaglandins such as arbaprostil, carboprost and prostacydin;-   antidepressives such as 8-hydroxychlorimipramine and    2-hydroxyimipramine;-   antihypertonics such as sotarol and fenoldopam;-   anticholinerogenics such as biperidine, carbidopa, procyclidin and    trihexyphenidal;-   antiallergenics such as cromolyn;-   glucocorticoids such as betamethasone, budenosid, chlorpredhison,    clobetasol, clobetasone, corticosteron, cortisone, cortodexon,    dexamethason, flucortolon, fludrocortisone, flumethasone,    flunisolid, fluprednisolon, flurandrenolide, flurandrenolon    acetonide, hydrocortisone, meprednisone, methylpresnisolon,    paramethasone, prednisolon, prednisol, triamcinolon and triamcinolon    acetonide;-   narcotic agonists and antagonists such as apomorphine,    buprenorphine, butorphanol, codein, cyclazacin, hydromorphon,    ketobemidon, levallorphan, levorphanol, metazocin, morphine,    nalbuphin, nalmefen, naloxon, nalorphine, naltrexon, oxycodon,    oxymorphon and pentazocin;-   stimulants such asmazindol and pseudoephidrine;-   anaesthetics such as hydroxydion and propofol;-   β-receptor blockers such as acebutolol, albuterol, alprenolol,    atenolol, betazolol, bucindolol, cartelolol, celiprolol, cetamolol,    labetalol, levobunelol, metoprolol, metipranolol, nadolol,    oxyptenolol, pindolol, propanolol and timolol;-   α-sympathomimetics such as adrenalin, metaraminol, midodrin,    norfenefrin, octapamine, oxedrin, oxilofrin, oximetazolin and    phenylefrin;-   β-sympathomimetics such as bamethan, clenbuterol, fenoterol,    hexoprenalin, isoprenalin, isoxsuprin, orciprenalin, reproterol,    salbutamol and terbutalin;-   bronchodilators such as carbuterol, dyphillin, etophyllin,    fenoterol, pirbuterol, rimiterol and terbutalin;-   cardiotonics such as digitoxin, dobutamin, etilefrin and    prenalterol;-   antimycotics such as amphotercin B, chlorphenesin, nystatin and    perimycin;-   anticoagulants such as acenocoumarol, dicoumarol, phenprocoumon and    warfarin;-   vasodilators such as bamethan, dipyrimadol, diprophyllin,    isoxsuprin, vincamin and xantinol nicotinate;-   antihypocholesteremics such as compactin, eptastatin, mevinolin and    simvastatin;-   miscellaneous drugs such as bromperidol (antipsychotic), dithranol    (psoriasis) ergotamine (migraine) ivermectin (antihelminthic),    metronidazole and secnizadole (antiprotozoals), nandrolon    (anabolic), propafenon and quinadine (antiarythmics), srotonin    (neurotransmitter) and silybin (hepatic disturbance).

The above mentioned monohydric nucleosides are an example of theprodrugs of the invention applied to chain hydroxy functions, typicallythe 5′ hydroxy function of the (pseudo)saccharide moiety of thenucleoside. However, the fatty acid free aspect of the invention is notlimited to the monohydric nucleosides disclosed above, but is alsoapplicable to L and D-nucleosides bearing di, tri and tetrahyric(pseudo)saccharides, such as those of the formula N-3:

where B is a natural or unnatural nucleotide base,

-   -   R_(N1) is O or —CH₂—, S    -   R_(N2) and R_(N3) are each H or R_(N2) is methylene or —CH(OH)—        and R_(N5) is a bond thereto, or R_(N2) and R_(N5) together are        a bond;    -   n is 0 or 1;    -   one of R_(N3) and R_(N4) comprises a linker-R₂ structure such as        those of formulae IIaa, II′aa, IIc′, IIe′, IIf*, id′ and the        other is hydrogen or a further linker-R₂ structure.

An alternative group drugs to which the invention is applicable includesthose of formula N-3a:

where B, NR3 and NR4 are as defined above.

An alternative group of drugs within the scope of the invention has theformula N-3b:

where B, RN3 and RN4 are as defined above and RN6 is fluoro and RN7 ishydrogen or RN6 and RN7 are both fluoro or RN6 and RN7 together definean exo-methenyl group. The preferred base is guanine in thisalternative.

A further group of nucleosides within the scope of the invention has theformula N-3c

where B, RN3 and RN4 are as defined above, RN8 and RN9 are fluoro (orone of them is fluoro and the other is hydrogen) or RN8 and RN9 togetherdefine exomethenyl or exomethenyl mono or di-subsituted with fluoro.These nucleosides have anticancer activity.

The invention is also applicable to other nucleosides having at leasttwo hydroxy groups, but outside the scope of formula N-3a-c, forinstance, 9-[3,3-dihydroxymethyl-4-hydroxy-but-1-yl]guanine as describedin WO 95/22330 and 9-[4-hydroxy-(2-hydroxymethyl)butyl]guanine asdescribed in EP 343 133. The invention is applicable to both L and Dstereo forms of the various nucleoside analogues

The compounds of the invention, especially cytosine or guaninederivatives where NR1 is oxygen, n is 1 and NR2 and NR5 define a ringare also active against certain retroviral infections, notably SIV,HIV-1 and HIV-2, and Hepatitis B virus. The compounds of the invention,especially cytosine, guanosine or 6-methoxyguanosine derivatives whereinNR1 is oxygen, n is 0 and NR2 and NR5 define an arabinose ring arepotent anticancer compounds.

The compounds of the invention, especially derivatives comprising a1,2,4-triazole-3-carboxamide base, where NR1 is O, NR2 is —CH(OH)—, NR3is a bond thereto and n is 0 (ribavirin) are expected to be activeagainst hepatitis C virus (HCV). Compounds comprising a substitutedbenzimidazole base, where NR1 is O, NR2 is —CH(OH)—, NR5 is a bondthereto and n is 0 (for instance Glaxo Wellcome's 1263W94 where the baseis 2-isopropylamin-5,6-dichloro-benzimidazol-3-yl) are expected to beactive against CMV. Compounds comprising an adenine base, where NR1 isO, NR2 is —CH(OH)—, NR5 is a bond thereto and n is 0 (vidarabine) areexpected to be active against HSV encephalitis. Compounds comprising a2-chloroadenine base with a 2′-deoxyribose sugar are expected to haveanticancer activity.

The nucleoside derivatives of the invention are particularly useful forguanine nucleoside and analogues which tend to have poorer uptake thanpyrimidine nucleosides. Accordingly B is preferably guanine or a guaninederivative.

A group of hydroxy bearing drugs which are particularly amenable to theprodrugs of the invention are the ring hydroxy compounds. By ringhydroxy is meant that the hydroxy function to which the prodrug of theinvention is bound is bonded directly onto an aromatic or non-aromatic,heterocyclic or carbocyclic ring structure.

Examples of ring hydroxy compounds include the cyclic urea HIV proteaseinhibitors, such as those described in WO 9843969, WO9820008, and WO9419329. Representative protease inhibitors include:

where R1 is NH₂ (DMP 450) or

Some examples of phenolic ring hydroxy compounds include the PETT NNRTIdiscussed below or the compound described in J Med Chem 35 3467 (1992):

Pancratistatin described in Anticancer Drug Design 10: 243 & 299 (1995)and Bioorg Med Chem Lett 6 157 1996:

has both phenolic and carbocyclic ring hydroxy functions. A furtheruseful drug with a combination of phenolic and carbocyclic hydroxyfunctions is etoposide:

as described in Bioorg Med Chem Lett 4 2567 (1994) and Clinical CancerRes 1 105 1995.

Representative phosphorous containing drugs include phosfestrol,(E)-(α,β-diethyl-4,4′-stilbenylen)bis(dihydrogenphosphate) andcytostatic metabolites such as phosphorylated cytarabin or gemcitabin,

Other phosphonates include antiviral nucleoside or nucleotide analoguessuch as PMEA, HPMPC, PMPA and the like or phosphates such as themonophosphates of those nucleoside analogues which requirephosphorylation for activity, such as ACV AZT, ddI, ddC, PCV, GCV, BVDU,FMAU, 3TC, FTC etc. As described above, certain mixed amino acid/fattyacid acyloxyalklphosphonates are described in our copending applicationPCT SE97 001903 and it should be thus appreciated that the prodrugs ofthe present invention are fatty acyl-free and/or apply the novel linkersdefined herein in the phosphonate nucleotide field.

Taking the phosphonate antivirals adefovir and cidovir as examples,prodrugs of the invention can be applied as shown in Formula PF2:

where

-   R₂ is the acyl residue of an aliphatic amino acid,-   R_(4L) and R_(4L)′ are independently H, C₁₋₃ alkyl, C₃₋₆cycloalkyl,    C₁₋₃alkyl-C₁C₆cycloalkyl phenyl or benzyl,-   R_(4R) and R_(4R)′ are independently H, C₁₋₃ alkyl or phenyl ql is    0-3, qr is 0-3,-   T is a bond, —NR₄— or —O—-   R₄ is H or C₁₋₃alkyl;-   ring is an optionally substituted aromatic or non-aromatic,    hetero-or carbocycle;-   base is a natural or unnatural nucleotide base, especially guanine,    adenine or cytosine, Rf3 is H or a further structure of the formula    II″b and Rf4 is H or CH₂OH.

Currently favoured values in formula PF2 include: R_(3R) and R_(3R)′ arepreferably H and/or R_(3L) and R_(3L)′ are preferably ethyl orespecially methyl. T is preferably —O— or more preferably a bond.Preferably qr is 1 or more preferably 0.

Thus a preferred group of phosphonate antivirals within the scope of theinvention include:

-   9-[2-phosphonomethoxy)ethyl]adenine,    mono(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine, mono(2-methyl-2-(L-valyloxy)    propionyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono(2-L-valyloxy)-DL-propionyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine, mono    [4-(L-valyloxy)-butanoyloxymethyl]ester,-   9-[2-phosphonomethoxy)ethyl]adenine, mono-(4-(L-valyloxy)    benzoyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(3-(3,4-di-(L-valyloxy)phenyl) propionyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(4-N-valyloxy)cyclohexanoyloxymethyl) ester-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester-   9-[2-phosphonomethoxy)ethyl]adenine,    mono(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine, mono(2methyl-2-(L-isoleucyloxy)    propionyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono(2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono(2-L-isoleucyloxy)-DL-propionyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-((2-(L-isoleucyloxy)-ethoxycarbonyloxy) methyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine, mono    [4-(L-isoleucyloxy)-butanoyloxymethyl] ester,-   9-[2-phosphonomethoxy)ethyl]adenine, mono-(4-(L-isoleucyloxy)    benzoyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(3-(3,4-di-(L-isoleucyloxy)phenyl) propionyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl) ester,-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(4-N-isoleucyloxy)cyclohexanoyloxymethyl) ester-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   9-[2-phosphonomethoxy)ethyl]adenine,    mono-(1-(2-L-isoleucyloxymethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester    the corresponding bis esters and pharmaceutically acceptable salts    thereof. A further preferred group comprises the corresponding    derivatives of PMPA and HPMPC.

A further group of phosphorous containing antivirals amenable to theinvention include foscarnet (phosphonoformate) and PAA(phosphonoacetate). Taking foscarnet as an example:

it will be apparent that linkers such as those of formula IId or II′dcan be applied to the carboxy function. Preferably, however, oradditionally, one or two linkers of formula IIb, II′b, IIe, II′e orespecially II″b can be applied to the phosphonate hydroxy functions todefine compounds such as:

Thus a preferred group of compounds comprises foscarnet derivatives ofthe formula PF1:

where

-   R₂ is the acyl residue of an aliphatic amino acid,-   R_(4L) and R_(4L)′ are independently H, C₁₋₃ alkyl, C₃₋₆cycloalkyl,    C₁₋₃alkyl-C₁C₆cycloalkyl phenyl or benzyl,-   R_(4R) and R_(4R)′ are independently H, C₁₋₃ alkyl or phenyl-   ql is 0-3, qr is 0-3,-   T is a bond, —NR₄— or —O—-   R₄ is H or C₁₋₃alkyl;-   ring is an optionally substituted aromatic or non-aromatic,    hetero-or carbocycle;-   and Rf1 is H or a further ester of formula II″b and Rf2 is H or a    conventional pharmaceutically acceptable ester.

Currently favoured values in Formula PF1 include: R_(4R) and R_(4R)′ arepreferably H and/or R_(4L) and R_(4L)′ are preferably ethyl orespecially methyl. T is preferably —O— or more preferably a bond.Preferably qr is 1 or more preferably 0. If Rf1 is a further ester it isconvenient if it is identical to other linker-R₂ moiety. Conventionalpharmaceutically acceptable esters for Rf2 include the methyl, ethyl andisopropyl esters.

A favoured group of compounds within formula PF1 include:

-   phosphonoformic acid,    mono(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl) ester,-   phosphonoformic acid,    mono(2-methyl-2-(L-valyloxy)propionyloxymethyl) ester,-   phosphonoformic acid,    mono(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   phosphonoformic acid,    mono(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   phosphonoformic acid, mono((1,3-di-valyloxy)propyl-2-oxycarbonyloxy    methyl) ester,-   phosphonoformic acid, mono(2-L-valyloxy)-DL-propionyloxymethyl)    ester,-   phosphonoformic acid,    mono-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   phosphonoformic acid, mono-((2-(L-valyloxy)-ethoxycarbonyloxy)    methyl) ester,-   phosphonoformic acid, mono [4-(L-valyloxy)-butanoyloxymethyl] ester,-   phosphonoformic acid, mono-(4-(L-valyloxy) benzoyloxymethyl) ester,-   phosphonoformic acid,    mono-(3-(3,4-di-(L-valyloxy)phenyl)propionyloxymethyl) ester,-   phosphonoformic acid,    mono-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl) ester,-   phosphonoformic acid, mono-(4-N-valyloxy)cyclohexanoyloxymethyl)    ester-   phosphonoformic acid,    mono-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   phosphonoformic acid,    mono-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester-   phosphonoformic acid, mono(2-methyl-2-(L-isoleucyloxymethyl)    propionyloxymethyl) ester,-   phosphonoformic acid,    mono(2-methyl-2-(L-isoleucyloxy)propionyloxymethyl) ester,-   phosphonoformic acid,    mono(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   phosphonoformic acid,    mono(2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   phosphonoformic acid,    mono((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   phosphonoformic acid, mono(2-L-isoleucyloxy)-DL-propionyloxymethyl)    ester,-   phosphonoformic acid,    mono-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   phosphonoformic acid, mono-((2-(L-isoleucyloxy)-ethoxycarbonyloxy)    methyl) ester,-   phosphonoformic acid, mono [4-(L-isoleucyloxy)-butanoyloxymethyl]    ester,-   phosphonoformic acid, mono-(4-(L-isoleucyloxy) benzoyloxymethyl)    ester,-   phosphonoformic acid, mono-(3-(3,4-di-(L-isoleucyloxy)phenyl)    propionyloxymethyl) ester,-   phosphonoformic acid, mono    (2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl) ester,-   phosphonoformic acid, mono-(4-isoleucyloxy)cyclohexanoyloxymethyl)    ester-   phosphonoformic acid,    mono-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   phosphonoformic acid,    mono-(1-(2-L-isoleucyloxymethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester    the corresponding bis esters, the corresponding compounds    additionally bearing a C-ethyl esters, and pharmaceutically    acceptable salts thereof.

A further class of phosphonates which are amenable to the invention andwhich share a structural similarity with phosphonoformic are theβ-phosphonocarboxylic acid farnesyl protein transferase inhibitors,especially those of the of the formula PF4:

where RF1 is H or a further structure of formula II″b

-   -   Rf2 is H or a conventional pharmaceutically acceptable ester,    -   Rf3 is a polyunsaturated, branched C₆₋₂₂ alkyl,

-   R₂ is the acyl residue of an aliphatic amino acid,

-   R_(4L) and R_(4L)′ are independently H, C₁₋₃ alkyl, C₃₋₆cycloalkyl,    C₁₋₃alkyl-C₁C₆cycloalkyl phenyl or benzyl,

-   R_(4R) and R_(4R)′ are independently H, C₁₋₃ alkyl or phenyl

-   ql is 0-3, qr is 0-3,

-   T is a bond, —NR₄— or —O—

-   R₄ is H or C₁₋₃alkyl;

-   ring is an optionally substituted aromatic or non-aromatic,    hetero-or carbocycle.

Currently favoured values in Formula PF4 include: R_(4R) and R_(4R)′ arepreferably H and/or R_(4L) and R_(4L)′ are preferably ethyl orespecially methyl. T is preferably —O— or more preferably a bond.Preferably qr is 1 or more preferably 0. If Rf1 is a further ester it isconvenient if it is identical to other linker-R₂ moiety. Conventionalpharmaceutically acceptable esters for Rf2 include the methyl, ethyl andisopropyl esters. A convenient polyunsaturated alkyl Rf3 has theformula:

Other structurally similar phosponates include α-phosphonosulphonatessuch as squalene synthase inhibitors of the formula PF5:

where RF1 is H or a further structure of formula II″b

-   -   Rf2 is H or a conventional pharmaceutically acceptable ester a        further structure of formula II″b    -   Rf3 is a polyunsaturated, branched C₆₋₂₂ alkyl,

-   R₂ is the acyl residue of an aliphatic amino acid,

-   R_(4L) and R_(4L)′ are independently H, C₁₋₃ alkyl, C₃₋₆cycloalkyl,    C₁₋₃alkyl-C₁C₆cycloalkyl phenyl or benzyl,

-   R_(4R) and R_(4R)′ are independently H, C₁₋₃ alkyl or phenyl

-   ql is 0-3, qr is 0-3,

-   T is a bond, —NR₄— or —O—

-   R₄ is H or C₁₋₃alkyl;

-   ring is an optionally substituted aromatic or non-aromatic,    hetero-or carbocycle.

Currently favoured values in Formula PF5 include: R_(4R) and R_(4R)′ arepreferably H and/or R_(4L) and R_(4L)′ are preferably ethyl orespecially methyl. T is preferably —O— or more preferably a bond.Preferably qr is 1 or more preferably 0. If Rf1 is a further ester it isconvenient if it is identical to other linker-R₂ moiety. Conventionalpharmaceutically acceptable esters for Rf2 include the methyl, ethyl andisopropyl esters. A convenient polyunsaturated alkyl Rf3 has theformula:

A particularly preferred group of phosphorous containing drugs are thebisphosphonates active in bone metabolism. Favoured bis-phosphonateshave the formula:

where

-   X is H, halo, hydroxy; and Y is-   a) C₁₋₁₀ alkyl, optionally substituted with heterocycle,    -   —NR_(a)R_(b), where R_(a) and R_(b) are independently hydrogen,        C₁₋₆ alkyl or join together to form a 5 to 7 membered ring,        optionally containing a further hetero atom,    -   OH, halo, —S(C₁₋₆ alkyl), phenyl, —C₁₋₇ cycloalkyl, (optionally        substituted with —NR_(a)R_(b) or OH);-   b) C₃₋₇ cycloalkyl, optionally substituted with —NR_(a)R_(b), OH,    halo, —S(C₁₋₆ alkyl), phenyl, morpholino or pyridyl;-   c) halo;-   d) piperidinyl;-   e) pyrrolidinyl;-   f) —S(C₁₋₆ alkyl), optionally substitued with —NR_(a)R_(b), OH, halo    or phenyl;-   g) —S-phenyl, optionally substituted with halo, nitro, C₁₋₆ alkyl    C₁₋₆ alkoxy, trifluormethyl, —CONRaR_(b) or —COOH.

Preferred bis-phosphonates include alendronate (X is hydroxy, Y isNH₂CH₂CH₂CH₂—), clodronate (X is chloro, Y is chloro), etidronate (X ishydroxy, Y is CH₃—), pamidronate (X is hydroxy, Y is NH₂CH₂CH₂—),ibandronate (X is hydroxy, Y is N (CH₂CH₂CH₂CH₂CH3)(CH₃)CH₂CH₂—),tiludronate (X is H, Y is 4-chlorophenylthio—), risedronate (X ishydroxy, Y is 3-pyridinylmethylene-) and zoledronate (X is hydroxy, Y is(2-(1H-imidazol-1-yl)methylene-)

Taking alendronate as an example:

it will be apparent that the drug contains several accessible functions(viz the hydroxy group at position 1, the amino group at position 4 andtwo esterifiable hydroxy groups on each phosphorous. Prodrugs inaccordance with the invention can thus be derivatised on one or more ofthese functions. For instance a linker such as those of Formula IIaabove, for instance when T is a bond or —O— and V is a bond can beesterified to the 1-hydroxy position or amide-bonded to the 4-aminoposition. In a favoured embodiment of the invention, however, theprodrugs of the invention are derivatised to the phosphonate groups.

Thus one to three linker structures of formula IIe, II′e, Va, Vb or mostpreferably II″b can be esterified to one or both of the phosphonates,especially one such linker structure on each phosphonate.

Preferred compounds within this bis-phosphonate aspect of the inventionthus include those of the formula A1:

wherein YY and XX have the following values:

NH₂(CH₂)₃— OH (alendronate) NH₂(CH₂)₂— OH (pamidronate)cycloheptylamino- H (cimadronate) chloro- chloro (clodronate)pyrrolidin-1-ylCH₂CH₂— OH (EB 1053) CH₃— OH (etidronate)methylpentylaminoCH₂CH₂— OH (ibandronate) dimethylaminoCH₂CH₂— OH(olpadronate) pyridin-3-ylCH₂— OH (risedronate) (4-chlorophenyl)-thio- H(tiludronate) imidazo-(1,2-a)pyridin-3-ylCH₂— OH (YH 529)1H-imidazol-1ylCH₂— OH (zoledronate)wherein amino groups on YY can be optionally substituted withconventional pharmaceutically acceptable amide groups such as—C(═O)C₁₋₆alkyl or an aminoacyl or peptidyl derivative, as described inWO 96/31227; and wherein at least one of Ra1-Ra4 is a structure of theformula

where

-   R₂ is the acyl residue of an aliphatic amino acid,-   R_(4L) and R_(4L)′ are independently H, C₁₋₃ alkyl, C₃₋₆cycloalkyl,    C₁₋₃alkyl-C₁C₆cycloalkyl phenyl or benzyl,-   R_(4R) and R_(4R)′ are independently H or C₁₋₃ alkyl-   ql is 0-3, qr is 0-3,-   T is a bond, —NR₄— or —O—-   R₄ is H or C₁₋₃alkyl;-   ring is an optionally substituted aromatic or non-aromatic,    hetero-or carbocycle;-   and the remainder of Ra1-4 are hydrogen or conventional    pharmaceutically acceptable esters.

In formula A-1, R_(4R) and R_(4R)′ are preferably H and/or R_(4L) andR_(4L)′ are preferably ethyl or especially methyl. T is preferably —O—or more preferably a bond. Preferably qr is 1 or more preferably 0.

Favoured compounds thus include;

-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di(2-L-valyloxy)-DL-propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    bis[4-(L-valyloxy)-butanoyloxymethyl] ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate, di-(4-(L-valyloxy)    benzoyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(3-(3,4-di-(L-valyloxy)phenyl) propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(4-valyloxy)cyclohexanoyloxymethyl) ester-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di(2-L-valyloxy)-DL-propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    bis[4-(L-valyloxy)-butanoyloxymethyl] ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(4-(L-valyloxy) benzoyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(3-(3,4-di-(L-valyloxy) phenyl)propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(4-valyloxy)cyclohexanoyloxymethyl) ester-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate    di(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di(2-L-valyloxy)-DL-propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    bis[4-(L-valyloxy)-butanoyloxymethyl] ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(4-(L-valyloxy) benzoyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(3-(3,4-di-(L-valyloxy) phenyl)propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(4-valyloxy)cyclohexanoyloxymethyl) ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester    and pharmaceutically acceptable salts thereof.

A further group of favoured compounds include:

-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono(2-(L-valyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono(2-L-valyloxy)-DL-propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate, mono    [4-(L-valyloxy)-butanoyloxymethyl] ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate, mono-(4-(L-valyloxy)    benzoyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(3-(3,4-di-(L-valyloxy) phenyl)propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(4-valyloxy)cyclohexanoyloxymethyl) ester-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono    (2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono    (2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono    ((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono    (2-L-valyloxy)-DL-propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono    [4-(L-valyloxy)-butanoyloxymethyl] ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(4(L-valyloxy) benzoyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(3-(3,4-di-(L-valyloxy) phenyl)propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(2-methyl-1-(L-valyloxy)-2-propoxycarbonylmethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(4-N-valyloxy)cyclohexanoyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydropyridine-3-carbonyloxymethyl)    ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate    mono(2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono(2-methyl-2-(L-valyloxy) propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono    (2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono    (2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   1-hydroxy-2-pyrid-3-yl)ethylidene bis-phosphonate,    mono(2-L-valyloxy)-DL-propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono    [4-(L-valyloxy)-butanoyloxymethyl] ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(4-(L-valyloxy) benzoyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(3-(3,4-di-(L-valyloxy) phenyl)propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(4-valyloxy)cyclohexanoyloxymethyl) ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester    and pharmaceutically acceptable salts thereof.

A further group of favoured compound include:

-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester,-   (4amino-1-hydroxybutylidine)-bisphosphonate,    di(2-methyl-2-(L-isoleucyloxy) propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di(2-(L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di(2-L-isoleucyloxy)-DL-propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-((2-(L-isoleucyloxy)-ethoxycarbonyloxy) methyl) ester,-   (4amino-1-hydroxybutylidine)-bisphosphonate,    bis[4-(-L-isoleucyloxy)-butanoyloxymethyl] ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate, di-(4-(L-isoleucyloxy)    benzoyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(3-(3,4-di-(L-isoleucyloxy) phenyl)propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(4-valyloxy)cyclohexanoyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    di-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di(2-methyl-2-(L-isoleucyloxy) propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di(2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di(2-L-isoleucyloxy)-DL-propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-((2-(L-isoleucyloxy)-ethoxycarbonyloxy) methyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    bis[4-(L-isoleucyloxy)-butanoyloxymethyl] ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(4-(L-isoleucyloxy) benzoyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(3-(3,4-di-(L-isoleucyloxy) phenyl)propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(4-isoleucyloxy)cyclohexanoyloxymethyl) ester-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    di-(1-(2-L-isoleucyloxymethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate    di(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di(2-methyl-2-(L-isoleucyloxy) propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di(2-(L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di(2-L-isoleucyloxy)-DL-propionyloxymethyl) ester,-   1-hydroxy-2-pyrid-3-yl)ethylidene bis-phosphonate,    di-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-((2-(L-isoleucyloxy)-ethoxycarbonyloxy) methyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    bis[4-(L-isoleucyloxy)-butanoyloxymethyl] ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(4-(L-isoleucyloxy) benzoyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(3-(3,4-di-(L-isoleucyloxy) phenyl)propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(4-N-isoleucyloxy)cyclohexanoyloxymethyl) ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    di-(1-(2-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester    and pharmaceutically acceptable salts thereof.-   A further group of favoured compounds include:-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono(2-methyl-2-(L-isoleucyloxymethyl)propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono(2-methyl-2-(L-isoleucyloxy) propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono(2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono(2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono(2-L-isoleucyloxy)-DL-propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-((2-(L-isoleucyloxy)-ethoxycarbonyloxy) methyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono[4-(L-isoleucyloxy)-butanoyloxymethyl] ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(4-(L-isoleucyloxy) benzoyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(3-(3,4-di-(L-isoleucyloxy) phenyl)propionyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl) ester,-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(4-isoleucyloxy)cyclohexanoyloxymethyl) ester-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   (4-amino-1-hydroxybutylidine)-bisphosphonate,    mono-(1-(2-L-isoleuxyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono(2-methyl-2-(L-isoleucyloxy) propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono    (2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono    (2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono    ((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate, mono    (2-L-isoleucyloxy)-DL-propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-((2-(L-isoleucyloxy)-ethoxycarbonyloxy) methyl) ester,-   1-hydroxy-2-(1H-imidazoly-1-yl)ethylidene-bis phosphonate,    mono[4-(L-isoleucyloxy)-butanoyloxymethyl] ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(4-(L-isoleucyloxy) benzoyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(3-(3,4-di-(L-isoleucyloxy) phenyl)propionyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl) ester,-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(4-isoleucyloxy)cyclohexanoyloxymethyl) ester-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl) ester-   1-hydroxy-2-(1H-imidazolyl-1-yl)ethylidene-bis phosphonate,    mono-(1-(2-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymetlbyl)    ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate    mono(2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono(2-methyl-2-(L-isoleucyloxy) propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono    (2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate, mono    (2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono((1,3-di-isleucyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono(2-L-isoleucyloxy)-DL-propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-((2-(L-isoleucyloxy)-ethoxycarbonyloxy) methyl) ester,-   1-hydroxy-2-pyrid-3-yl)ethylidene bis-phosphonate,    mono[4-(N-CBz-L-isoleucyloxy)-butanoyloxymethyl] ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(4-(L-isoleucyloxy) benzoyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(3-(3,4-di-(L-isoleucyloxy) phenyl)propionyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl) ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(4-isoleucyloxy)cyclohexanoyloxymethyl) ester-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(1-isoleucyloxy-2-methylpropane-2-aminocarbonyloxymethyl)    ester,-   1-hydroxy-2-(pyrid-3-yl)ethylidene bis-phosphonate,    mono-(1-(2-L-isoleucyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    ester    and pharmaceutically acceptable salts thereof.

A still further preferred group of prodrugs of the invention are thosebased on fosinoprilate having the formula PF3:

where

-   R₂ is the acyl residue of an aliphatic amino acid,-   R_(4L) and R_(4L)′ are independently H, C₁₋₃ alkyl, C₁₋₆cycloalkyl,    C₁₋₃alkyl-C₁C₆cycloalkyl phenyl or benzyl,-   R_(4R) and R_(4R)′ are independently H or C₁₋₃ alkyl-   ql is 0-3, qr is 0-3,-   T is a bond, —NR₃— or —O—-   R₃ is H or C₁₋₃alkyl;-   ring is an optionally substituted aromatic or non-aromatic,    hetero-or carbocycle;    and pharmaceutically acceptable salts thereof.

In formula PF3, R_(4R) and R_(4R)′ are preferably H and/or R_(4L) andR_(4L)′ are preferably ethyl or especially methyl. T is preferably —O—or more preferably a bond. Preferably qr is 1 or more preferably 0.

Favoured compounds within formula PF3 thus include

-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-methyl-2-(L-valyloxymethyl) propionyloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-methyl-2-(L-valyloxy) propionyloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    ((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-L-valyloxy)-DL-propionyloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    ((2-(L-valyloxy)-ethoxycarbonyloxy) methyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    [4-(L-valyloxy)-butanoyloxymethyl] ester,-   (4S)-4-cyclohexyl-1[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (4-(L-valyloxy) benzoyloxymethyl) ester,-   (4S)-4cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (3-(3,4-di-(L-valyloxy) phenyl)propionyloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl) ester,-   (4-N-valyloxy)cyclohexanoyloxymethyl) ester-   (1-valyloxy-2-methylpropane-2-aminocarbonyloxymethyl)-   (1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)-   (4S)-4cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-methyl-2-(L-isoleucyloxymethyl) propionyloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-methyl-2-(L-isoleucyloxy) propionyloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-(L-isoleucyloxy)-3-methyl-(S)-(+)-butyryloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-(-L-isoleucyloxy)-2-phenyl-DL-acetyloxymethyl) ester,-   (4S)-4cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    ((1,3-di-isoleucyloxy)propyl-2-oxycarbonyloxy methyl) ester,-   (4S)-4cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-L-isoleucyloxy)-DL-propionyloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (5-(L-isoleucyloxy)-2,2-dimethylvaleryloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    ((2-(L-isoleucyloxy)-ethoxycarbonyloxy) methyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    [4-(L-isoleucyloxy)-butanoyloxymethyl] ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (4-(L-isoleucyloxy) benzoyloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (3-(3,4-di-(L-isoleucyloxy) phenyl)propionyloxymethyl) ester,-   (4S)-4-cyclohexyl-1-[[(R)(4-phenylbutyl)phosphinyl]acetyl]-L-proline,    (2-methyl-1-(L-isoleucyloxy)-2-propoxycarbonyloxymethyl) ester,-   (4-N-valyloxy)cyclohexanoyloxymethyl) ester-   (1-valyloxy-2methylpropane-2-aminocarbonyloxymethyl)-   (1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)    and pharmaceutically acceptable salts thereof.

A further phosphonate compound amenable to the prodrugs of the inventionare the neutral endopeptidase inhibitors such as CGS-24592 (Novartis),preferably those of the formula PF6:

where RF1 is H or a further structure of formula II″b

-   -   Rf2 is H or a conventional pharmaceutically acceptable ester,

-   R₂ is the acyl residue of an aliphatic amino acid,

-   R_(4L) and R_(4L)′ are independently H, C₁₋₃alkyl, C₃₋₆cycloalkyl,    C₁₋₃alkyl-C₁C₆cycloalkyl phenyl or benzyl,

-   R_(4R) and R_(4R)′ are independently H or C₁₋₃ alkyl

-   ql is 0-3, qr is 0-3,

-   T is a bond, —NR₄— or —O—

-   R₄ is H or C₁₋₃alkyl;    ring is an optionally substituted aromatic or non-aromatic,    hetero-or carbocycle.

Currently favoured values in Formula PF6 include: R_(4R) and R_(4R)′ arepreferably H and/or R_(4L) and R_(4L)′ are preferably ethyl orespecially methyl. T is preferably —O— or more preferably a bond.Preferably qr is 1 or more preferably 0. If Rf1 is a further ester it isconvenient if it is identical to other linker-R₂ moiety. Conventionalpharmaceutically acceptable esters for Rf2 include the methyl, ethyl andisopropyl esters.

A further convenient Drug for applying the prodrugs of the invention isthe anti-Parkinsonian agent levodopa:

This drug has four accessible functions for applying the prodrugs of theinvention, namely the 3 and 4 hydroxy groups on the phenyl and the aminoand carboxy functions on the side chain.

A structure of the formula IIa or II″b be esterified to one or both ofthe aromatic hydroxyl functions or amide-bonded to the levodopa aminofunction. A trifunctional linker of Formula III or Formula IId, can becarbonyl bonded to the levodopa carboxyl function. Such “blocked”carboxyl levodopa compounds are conceivably less susceptible to in vivoperipheral decarboxylation than levodopa and may thus allow thediminution or omission of the customarily coadministered decarboxylaseinhibitors such as carbidopa.

A further convenient Drug for applying the prodrugs of the invention ischromoglycate, also known as cromolyn, useful in the treatment ofasthma, allergic rhinitis, mastocytosis, ulcerative colitis andinflammatory bowel disease:

It will be apparent that cromolyn has three accessible functionssuitable for applying the prodrugs of the invention. In particular, alinker of the formula IId can be carbonyl linked to either of thecarboxy groups. As cromolyn is a symmetric compound it may beadvantageous to bond a respective linker to each of the carboxyl groups.Alternatively or additionally, a linker of the formula IIa, II′a, IId,II′d such as those wherein T is a bond or —O— and V is a bond can beesterified to the hydroxy group depending from the propylene bridge,optionally in conjunction with conventional pharmaceutical esters on thecarboxy groups.

A further group of Drugs which are amenable to the prodrugs of theinvention are the pain-killer opiates such as morphine:

Morphine and many of its analogues have a pair of hydroxy functionsaccessible to the prodrug approach of the invention. For instance astructure of formula IIa wherein T is a bond or —O— and V is a bondwould be convenient for esterification with the 3 and/or 6 hydroxygroups.

A further convenient group of compounds include the macrolideantibiotics such as erythromycin and roxitromycin and antibacterialglycopeptides such as vancomycin.

A further convenient group of Drugs for applying the prodrugs of theinvention are the rifamycin antibiotics:

wherein the asterisks define the requisite number of aromatic bonds,including

-   rifampicin (R_(a) is OH, R_(b) is —CH═N-(4-N-methylpiperazine),    R_(c) is hydroxy),-   rifamide (R_(a) is OCH₂CONH(C₂H₅)₂, R_(b) is hydrogen, R_(c) is    hydroxy),-   rifamycin B (R_(a) is —OCH₂COOH, R_(b) is hydrogen, R_(c) is    hydroxy),-   rifamycin O (R_(a) is -1,3-dioxolan4-on)-2-yl, R_(b) is hydrogen,    R_(c) is hydroxy),-   rifamycin S (R_(a) is ═O, R_(b) is hydrogen, R_(c) is ═O),-   rifamycin SV (R_(a) is —OH, R_(b) is hydrogen R_(c) is —OH),-   rifaximin (R_(a) and R_(b) together define a structure:    R_(c) is hydroxy), and rifabutinum (R_(a) and R_(b) together define    a structure:    R_(c) is ═O).

It will be apparent that the rifamycins have a number of free hydroxylsand secondary amines available for esterification or amide bonding withrespective linker-R₂ groups in accordance with the invention such asthose of Formula II′a or Formula IIa above, which linker group is bondedto one of said hydroxy or amino groups.

A further group of Drugs which are amenable to the prodrugs of theinvention is the cephalosporin antibiotics:

Representative cephalosporins include:

-   cefpodoxime (R_(a) is    [(2-amino-4-thiazolyl)(methoximino)acetyl]amino-, R_(b) is H, R_(c)    is ethyl),-   cefaclor (R_(a) is aminophenylacetylamino, R_(b) is H, R_(c) is    chloro),-   cefadroxil (R_(a) is [amino-(4-hydroxyphenyl)acetyl]amino, R_(b) is    H, R_(c) is methyl);-   cefamandole (R_(a) is [amino-(4-hydroxyphenyl)acetyl]amino, R_(b) is    H, R_(c) is [1-methyl-1H-tetrazol-5-yl)thio]methyl);-   cefatrizine, (R_(a) is is [amino-(4-hydroxyphenyl)acetyl]amino,    R_(b) is H, R_(c) is [1H-1,2,3-triazol-4-ylthio]methyl);-   cefazedone (Ra is [(3,5-dichloro-4-oxo-1(4H)-pyridinyl)acetyl]amino,    R_(b) is H, R_(c) is [(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl),-   cefazolin (Ra is (1H-tetrazol-1-ylacetyl)-amino Rb is H, Rc is    [(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl,-   cefbuparazone (Ra is    [2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxy-1-oxobutyl]amino,    Rb is OCH₃, Rc is [(1-methyl-1H-tetrazoly-5yl)thio]methyl,-   cefixime Ra is    [(2-amino-4-thiozolyl)[carboxymethoxy)imino]acetyl]amino, Rb is H,    Rc is —CH═CH₂),-   cefmonoxime, (Ra is    [(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino, Rb is h, rc is    [(1-methyl-1H-tetrazol-5-yl)thio]methyl),-   cefmetazole ([[(cyanomethyl)thio]acetyl]amino, Rb is H, Rc is    [1-methyl-1H-tetrazol-5-yl)thio]methyl),-   cefminox (Ra is [[(2-amino-2-carboxyethyl)thio]acetyl]amino, Rb is    OCH₃, Rc is is [1-methyl-1H-tetrazol-5-yl)thio]methyl),-   cefodoxime (Ra is [(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino,    Rb is H, Rc is    [[5-(carboxymethyl)-4-methyl-2-thiazolyl]thio]methyl),-   cefonicid (Ra is (hydroxyphenylacetyl)amino, Rb is H, Rc is    [[1-8sulfomethyl)-1H-tetrazol-5-y]thio]methyl),-   cefoperazone (Ra is    [[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-hydroxyphenyl)acetyl]amino,    Rb is H, Rc is [(1-methyl-1H-tetrazol-5-yl)thio]methyl),-   ceforanide (Ra is [[2-(aminomethyl)phenyl]acetyl]amino, Rb is H, Rc    is [[1-(carboxymethyl)-1H-tetrazol-5-yl]thio]methyl),-   cefotaxime (Ra is [(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino,    Rb is H, Rc is (acetyloxy)methyl),-   cefotetan (Ra is    [[4-(2-amino-1-carboxy-2-oxoethylidine)-1,3-dithietan-2-yl]carbonyl]amino,    Rb is OCH₃, Rc is [(1-methyl-1H-tetrazol-5-yl)thio]methyl, Rc is    [(1-methyl-1H-tetrazol-5-yl)thio]methyl),-   cefotiam (Ra is [(2-amino-4-thiazolyl)acetyl]amino, Rb is H, Rc is    [[1-[2-(dimethylamino)ethyl]-1H-tetrazol-5-yl]thio]methyl),-   cefoxitin (Ra is (2-thienylacetyl)amino, Rb is OCH₃, Rc is    [aminocarbonyl)oxy]methyl),-   cefpimizole (Ra is    [[[(5-carboxy-1H-imidazol-4-yl)carbonyl]amino]phenylacetyl]amino, Rb    is H, Rc is (4′-(2-sulfoethyl)pyridinium) methyl hydroxide inner    salt,-   cefpiramide (Ra is    [[[(4-hydroxy-6-methyl-3-pyridinyl)carbonyl]amino](4-hydroxyphenyl)acetyl]amino,    Rb is H, Rc is [(1-methyl-1H-tetrazol-5-yl)thio]methyl),-   cefroxadine (Ra is (amino-1,4-cyclohexadien-1-yl-acetyl)amino, Rb is    H, Rc is OCH₃),-   cefsulodin (Ra is (phenylsulfoacetyl)amino, Rb is H, Rc is    (4′-carbamoyl pyridinium)methyl hydroxide inner salt),-   ceftazidime (Ra is    [(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino,    Rb is H, Rc is pyridiniummethyl hydrochloride inner salt),-   cefteram (Ra is [(2-amino-4-thiazolyl)methoxyimino)acetyl]amino, Rb    is H, Rc is (5-methyl-2H-tetrazol-2-yl)methyl),-   ceftezole (Ra is (1H-tetrazol-1-ylacetyl)amino, Rb is    (1,3,4-thiadiazol-2-ylthio)methyl),-   ceftibuten (Ra is    [2-(2-amino-4-thiazolyl)-4-carboxy-1-oxo-2-butenyl]amino, Rb is H,    Rc is H)-   ceftiofur (Ra is [(2-amino-4-thiazoyl)(methoxyimino)acetyl]amino, Rb    is H, Rc is [(2-furanylcarbonyl)thio]methyl),-   ceftizoxime (Ra is [(2-amino-4thiazolyl)(methoxyimino)acetyl]amino,    Rb is H, Rc is H),-   ceftriaxone (Ra is [(2-amino-4-thiazolyl)methoxyimino)acetyl]amino,    Rb is H, Rc is    [1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl)thio]methyl),-   cefuroxime (Ra is [2-furanyl(methoxyimino)acetyl]amino, Rb is H, Rc    is [(aminocarbonyl)oxy]methyl),-   cefuzonam (Ra is [(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino,    Rb is H, Rc is (1,2,3-thiadiazol-5-ylthio)methyl),-   cephacetrile (Ra is (cyanocetyl)amino, Rb is H, Rc is    (acetyloxy)methyl),-   cephalexin (Ra is (aminophenylacetyl)amino, Rb is H, Rc is methyl),-   cephaloglycin (Ra is (aminophenylacetyl)amino, Rb is H, Rc is    (acetyloxy)methyl),-   cephaloridine (Ra is (2-thienylacetyl)amino, Rb is H, Rc is    pyridinium methyl hydroxide inner salt),-   cephalosporin C (Ra is (5-amino-5-carboxy-1-oxopentyl)amino, Rb is    H, Rc is (acetyloxy)methyl),-   cephalothin (Ra is (2-thienylacetyl)amino, Rb is H, Rc is    (acetyloxy)methyl), cephamycin A (Ra is    (5-amino-5-carboxy-1-oxopentyl)amino, Rb is OCH₃ Rc is    —CH₂OCOC(OCH₂)═CH—(4-oxysulphyl)phenyl),-   cephamycin B (Ra is (5-amino-5-carboxy-1-oxopentyl)amino, Rb is OCH₃    Rc is —CH₂OCOCC(OCH₃)═CH—(4-hydroxy)phenyl),-   cephamycin C (Ra is (5-amino-5-carboxy-1-oxopentyl)amino, Rb is OCH₃    Rc is —CH₂OCONH₂)-   cephapirin (Ra is [(4-pyridinylthio)acetyl]amino, Rb is H, Rc is    (acetyloxy)methyl),-   cephradine (Ra is (amino-1,4-cyclohexadien-1-yl-acetyl)amino, Rb is    H, Rc is CH₃).

Common for the above cephalosporins is the presence of a carboxy groupat the 2-position which is amenable to derivation with a linker group,in particular those of the Formula III & IIId and IId & IId definedabove. The above listed Ra, Rb and Rc groups may also be combined invarious permutations and the invention includes prodrugs of all suchcephalosporins.

A further group of Drugs which are amenable to the prodrugs of theinvention are the anticholinesterases such as tacrine:

where R is H or OH. It will be apparent that the tacrine itself (R═H)has a free amine group suitable for derivatisation with a linker-R₂group such as those of Formula IIa, for instance when T is a bond or —O—and V is a bond. The tacrine metabolite (R═OH), which is also active invivo has an additional hydroxy function which can alternatively oradditionally be derivatised with a linker such as those of Formula IIa,for instance when T is a bond or —O— and V is a bond.

A further group of Drugs which are amenable to the prodrugs of theinvention are the sulphonamide diuretics such as furosemide:

It will be apparent that furosemide has a free carboxylic function, aprimary amine and a secondary amine amenable to the prodrugs of theinvention. In particular an R₁ bearing linker, such as those of FormulaIII, III′ or Formula IId. II′d can be carbonyl linked to the freecarboxy function. Alternatively or additionally, an R₂ bearing linker,such as those of Formula IIa or II′a, for instance where T is a bond or—O— and V is a bond can be amide bonded to the primary and/or secondaryamine groups.

A further group of Drugs amenable to the prodrugs of the inventioninclude the α-1 and β-blocker carvedilol compounds:

Carvedilol has a free hydroxy function, a secondary heterocyclic amineand a further secondary amine on the side chain, which are amenable tothe prodrugs of the invention, such as those of Formula II′a, forinstance where T is a bond or —O— and V is a bond which is in turnlinked to the hydroxy and/or the ring amine and/or the side chain aminefunctions on carvedilol.

A further group of Drugs which are amenable to the prodrugs of theinvention are the hypolipaemic statins, such as flustatin or compoundsof the formula:

such as pravastatin (Ra═H, Rb═OH, Rc═H, Rd═OH) and simvastatin (Ra═CH₃,Rb═CH₃, Rc and Rd together define a bond).

Taking simvastatin as an example, it will be apparent that there is afree side chain hydroxyl which is available for linkage with an R₂bearing linker, such as those of Formula IIa, for instance where T is abond or —O— and V is a bond.

The statin pravastatin also bears a corresponding hydroxy function andcan be derivatised with a linker in the same fashion. Pravastatin alsobears a ring hydroxyl and a further side chain hydroxyl function whichcan be derivatised with a linker in a corresponding fashion. Pravastatinalso bears a carboxyl function which can additionally or alternativelybe derivatised with an R₂ bearing linker such as those of Formula III,III′ or Formula IId, IId′.

A further group of Drugs which are amenable to the prodrugs of theinvention are peptides and pseudopeptides such protease inhibitorsincluding antifibrinolytics like aprotinin or peptidomimetic aspartylprotease inhibitors such as renin inhibitors. Other peptide Drugsinclude hormones such as vasopressins. Taking vasopressins as anexample, peptide Drugs may be cyclic oligopeptides consisting solely ofamino acids such as desmopressin or oxytocin, wherein the N and Cterminals represent accessible functions for derivatisation inaccordance with the invention. Additionally many peptide drugs includeamino acids with side chains bearing accessible functions such asarginine, serine or aspartate. Alternatively a peptide Drug,particularly peptidomimetics can be derivatised with non-amino acidstructures bearing accessible functions such as somatostatin octreotide.

Useful oligopeptides for derivisation according to the invention includeMK383, an Arg-Gly-Asp analogue useful as an antithrombotic, DADLE(Tyr-D-Ala-Gly-Phe-D-Leu), an encephalin analogue and NISIN.

An exemplary group of protease inhibitors amenable to the inventioncomprises the HIV protease inhibitors bearing one or more chain hydroxyfunctions and/or one or more ring hydroxy functions such as theindanolamine terminal group in Mercks indinavir:

Favoured prodrugs of indinavir in accordance with the invention include[1-(1S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-butyryloxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl-D-erythro-pentonamide.

A further indanol based HIV protease inhibitors is Novartis/BMS SDZ PRI053:

A further group of HIV protease inhibitors include the hexose derivedcompounds described in WO 98/45330, the contents of which are herebyincorporated by reference. These compounds typically have the generalformula I:

wherein:

-   A′ and A″ are independently a group of the formula II:    wherein:-   R′ is H, CH₃, C(CH₃)₂, —OR¹, —N(R′)₂, —N(R^(a))OR¹ or -DP-   R′″ is H, CH₃; R¹ is H, C₁-C₃ alkyl;-   D is a bond, C₁₋₃ alkylene, —C(═O)—, —S(O)— or —S(O)₂—;-   P is an optionally substituted, mono or bicyclic carbo- or    heterocycle;-   R″ is H, any of the sidechains found in the natural amino acids,    carboxacetamide, or a group (CH₂)_(n)DP;-   M is a bond or —C(═O)N(R′″)—;-   Q is absent, a bond, —CH(OH)— or —CH₂—;-   or R″ together with Q, M and R′ define an optionally substituted 5    or 6 membered carbo- or heterocyclic ring which is optionally fused    with a further 5 or 6 membered carbo- or heterocyclic ring;-   with the proviso that R′ is —OR^(a), —N(CH₃)₂, —N(R¹)OR¹ or -DP if M    is a bond and Q is absent;-   X is H, OH, OCH₃;-   Y is H, OH, OCH₃, but X and Y are not both H;-   Z′ and Z″ are independently —(CH₂)_(m)P where P is as defined above;-   and n and m are independently 0,1 or 2,    and pharmaceutically acceptable salts thereof.

Carbocyclic groups for R′ as -DP and/or Z′/Z″ and/or the optionalsubstituents thereto may be saturated, unsaturated or aromatic andinclude monocyclic rings such as phenyl, cyclohexenyl, cyclopentenyl,cyclohexanyl, cyclopentanyl, or bicyclic rings such as indanyl, napthyland the like.

Heterocyclic groups for R′ as -DP and/or Z′/Z″ and/or the optionalsubstituents thereto may be saturated, unsaturated or aromatic and have1 to 4 hetero atoms including monocyclic rings such as furyl, thienyl,pyranyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, isothiazolidinyl, and the like or bicyclicrings especially of the above fused to a phenyl ring such as indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,benzothienyl etc. The carbo or heterocyclic ring may be bonded via acarbon or via a hetero atom, typically a nitrogen atom, such asN-piperidyl, N-morpholinyl etc.

Disclosed embodiments of Formula II for the A′/A″ groups of thecompounds of formula I include those of the formula IIa:

where n is 1 or 2 and R′ is alkyloxy, preferably methyloxy, or thosewhere n is 0 and R′ is methyl.

Other disclosed groups of formula II include IIb below

An alternative configuration for the A′/A″ groups of the compounds ofthe invention includes groups of the formula IIc:

where Q is a bond, methylene or —C(OH)— and R′ is —OR^(a), —N(R^(a))₂,—NR^(a)OR^(a), where R^(a) is H or C₁-C₃ alkyl, or a carbo- orheterocyclic group including N-piperidine, N-morpholine, N-piperazine,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl etc.

A subset of compounds within formula IIc has the formula IId:

where R^(d) is hydrogen or methyl (that is a valyl or isoleucyl sidechain) and R^(c) is

where X is methylene, O, S, S═O, S(═O)₂ or NH or R^(c) is —N(CH₃)₂,—NHOH, —NHOMe, —NHOEt, —NMeOH, —NMeOMe etc.

In each of formulae IIa, IIb and IIc, R″ is hydrogen, methyl, ethyl,isopropyl, cycloalkyl such as cyclopropyl, cyclobutyl or cyclohexyl,cycloalkenyl, benzyl, carboxacetamide or 4-imidazolylmethy, any of whichmay be substituted as defined above. Preferred R″ groups include theside chains found in the natural amino acids, especially those ofleucine, asparagine, histidine or proline. The most preferred R″ groupsfor formula IIa, IIb, IIc and IId are the isoleucyl and especially thevalyl side chain.

R′ will vary depending on the nature of Q and/or M, if present, and mayfor instance be selected from hydrogen, methyl, ethyl, isopropyl, R^(c)as defined above, valinol, a heterocycle such as pyridyl, thiazole,oxazole, imidazole, N-piperidine, N-morpholine, N-piperazine, pyrrolyl,imidazolyl, pyrazolyl, pyrimidyl, pyrazinyl, any of which R′ groups maybe substituted as defined for Z′/Z″ below.

Further disclosed A′/A″ groups include those of formula II where R″, Q,M and R′ together define an optionally substituted 5 or 6 memberedcarbo- or heterocylic ring. A preferred group within this definitioninclude groups within formula III:

where

-   R′″ is as defined above,-   R¹ is H, NR⁴R⁴, C(═O)R³, CR³R⁴ or a monocyclic, optionally    substituted carbo- or heterocycle;-   R² is OH, or together with R¹ is ═O, or if R¹ is NR⁴R⁴, then R² may    be H;-   R³ is H, halo, C₁-C₃ alkyl, OR⁵, NR⁴R⁴;-   R⁴ is H, C₁-C₃ alkyl;-   R⁵ is H or a pharmaceutically acceptable ester;-   R⁶ is OH, NH₂, carbamoyl or carboxy;-   R⁷ is hydrogen, C₁-C₄ straight or branched alkyl or together with    the adjacent carbon atoms forms a fused phenyl or heteroaromatic    ring;

Preferred groups of formula III include aminoindanol and1-amino-azaindan-2-ol, that is moieties of the formulae:

This aspect of the present invention thus provides compounds of theformula IV:

where A′, A″, Z′ and Z″ are as defined above, one of R_(x′) and R_(x″)is H, OH or OCH₃ and the other one of R_(x′) and R_(x″) is a group ofthe formula —O-L-R_(y) where R_(y) is the acyl residue of an aliphaticamino acid and L is a bifunctional linker group.

With the expression “bifunctional linker group” is meant a group whichbears a function amenable to an acyl bond with the carboxy funtion ofthe amino acid derivative R_(y) and is also able to bond with an hydroxyfunction at the 3 or 4 position of the alkyl backbone of the structureof formula III. Exemplary L groups include an alkoxy moiety such as—CH₃O—, —CH(CH₃)O—, C(CH₃)₂O— and the like. Other exemplary L groupsinclude an alkoxyalkoxy moiety such as —CH₃O-Alk-O—, —CH(CH₃)O-Alk-O—,C(CH₃)₂O-Alk-O, where Alk is a C₁-C₆ branched or straight chainsaturated or unsaturated alkylene group, such as methylene, ethylene,1,1bismethylethylene and the like. Other exemplary L groups includederivatives of hydroxyalkanoic acids, where the carboxy function isacylated to the hydroxy function at the 3 or 4 position of the backboneof the structure of formula III, while the hydroxy function is availablefor acylation with the carboxy function of the amino acid group R_(y).Convenient hydroxyalkanoic acids include those derived from α-hydroxyω-carboxylic acids such as carbonic acid, glycollic acid,hydroxypropanoic acid, hydroxybutyric acid, hydroxyvaleric acid orhydroxycaproic acid.

A number of convenient bifunctional linker groups are described in SE9801216-4 which is hereby incorporated by reference, and also thedisclosure of PCT/SE98/01467, also incorporated herein by reference.

Linkers prepared from ω-hydroxybutyric derivatives are convenient aswith these compounds hydrolysis and removal of the R_(y) group in vivoleaves a reactive terminal radical which will tend to cyclize and promptthe effective release of the mother protease inhibitor. Similarly,linkers of the formula L_(a):

are convenient as enzymatic or spontaneous hydrolysis of a first of theR_(y) groups will result in an active terminus able to curl back andattack the acyl linkage to the mother compound thus promotingspontaneous release of the linker fragment. Other convenient linkersalong the same principle have the formula L_(b) or L_(c):

Preferred R_(y) groups include those derived from L-alanine, L-leucineand especially L-isoleucine and L-valine.

Favoured mother compounds within Formula IV include those of the formulaIVA:

where R_(d′) and R_(d″) are independently the side chain of an aliphaticL-amino acid, especially those of valyl or isoleucyl, one of R_(x′) andR_(x″) is hydroxy or hydrogen and the other is —O-L-R_(y), and R_(z) andR_(z′) are independently H, halo, amino, mercapto oxo, nitro, NHC₁-C₆alkyl, N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆alkanoyl, C₁-C₆ alkoxy, thioC₁-C₆ alkyl, thioC₁-C₆ alkoxy, hydroxy,hydroxyC₁-C₆ alkyl, haloC₁-C₆ alkyl, aminoC₁-C₆ alkyl, cyano, carboxyl,carbalkoxy, carboxamide, carbamoyl and the like, any of which alkylmoieties being optionally fluoro substituted, or an optionallysubstituted 5 or 6 membered carbocyclic or heterocyclic ring structure,such as cyclohexanyl, cyclohexenyl, phenyl, furyl, thienyl, pyranyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, isothiazolidinyl, and the like. The ringstructure may be bonded via a carbon atom or a hetero nitrogen. The ringstructure may itself substituted with substituents as definedimmediately above.

X ray crystallography indicates that there is significant scope forbulky substitution at R_(z′) and/or R_(z″) with (optionally substituted)groups such as para-phenyl, para-pyrid-2-yl, para-pyrid-3yl,para-thien-2-ylyl, parathien-3yl, para-pyrimid-2-y, para-pyrimid-3-yl,para-pyrimid-4-yl and parathiazol-2-yl.

Alternatively or additionally R_(z′) and/or R_(z″) can comprise asmaller substituent intended for interaction with adjacent portions ofthe molecule. For instance, an ortho-fluoro group can hydrogen bond withany hydroxy groups present in A′ or A″, thus serving to preventhydrophobic collapse and/or functioning as a pseudoscaffold. This isbest seen with the compounds of Formula IIIB below.

Exemplary compounds within Formula IVA thus include:

-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)hexanediamide-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-((L-valyloxy)-cis-but-2-enoyl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)hexanediamide-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)fluorobenzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)    hexanediamide,-   N1,N6-di    [(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxy-(1-methyl)methyloxy)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-isoleucyloxy)pentanoyl)hexanediamide,-   N1    ,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-isoeucyloxymethyl)benzoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoelucyloxy-(1-methyl)methyloxy)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)    hexanediamide-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-isoleuclyloxy)pentanoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleuclyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-isoleuclyloxymethyl)benzoyl)    hexanediamide-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)hexanediamide-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzyl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)    hexanediamide-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)    hexanediamide,-   N1    ,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,-   N₁,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxy-(1-methyl)methyloxy)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy4-O-(5-(L-isoleucyloxy)pentanoyl)hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy4-O-(2-(L-isoleucyloxymethyl)benzoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(metylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoleucyloxy-(1-methyl)methyloxy)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)    hexanediamide-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-isoleuclyloxy)pentanoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S)-2-methyl-1-(methylcarbamoyl)butyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-isoleucyloxymethyl)benzoyl)    hexanediamide,

A variant of this aspect of the invention provides compounds generallyin accordance with Formula IVA, but wherein one or both R_(d) comprisean isobutyl moiety. The mother compounds of this variant are preparedwith the dilactone opening procedure described in PCT/SE98/00622,employing L-tert-leucine methylamide (CAS reg nr. 89226-12-0). Thesemother compounds are themselves novel and define a further aspect of theinvention.

Preferred compounds within thus variant include:

-   N1,N6-di[(1S)-2,2    dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)hexanediamide-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy4-O-(2-(L-valyloxymethyl)benzoyl)hexanediamide-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)methyloxy)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)    hexanediamide-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy4-O-(4-(L-valyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxy-(1-methyl)methyloxy)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide-   N1,N6-di[(1S)-2,2-diethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-isoleucyloxy)pentanoyl)hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamol)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoeucyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-isoeucyloxymethyl)benzoyl)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-(L-isoelucyloxy-(1-methyl)methyloxy)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucylaxy)propionyl)    hexanediamide-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3yl)benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy-4-O-(5-(L-isoleuclyloxy)pentanoyl)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy4-O-(4-(L-isoleuclyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S)-2,2-dimethyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(thien-3-yl)benzyloxy)-3-hydroxy4-O-(2-(L-isoleuclyloxymethyl)benzoyl)    hexanediamide.

An alternative preferred group of compounds of the invention are thoseof Formula IVB:

where R_(x′), R_(x″), R_(z′) and R_(z″) are as defined above and whereinthe ring atom adjacent one or both asterisks is optionally replaced by—N— to define a fused cyclopentanylpyridyl ring.

Currently preferred R_(z′) and R_(z″) groups in Formula IV include orthohalogen, or phenyl, pyridyl, pyrimidyl, thiazolyl or thienyl in the paraposition relative to the linkage to the benzyloxy linkage. Especiallypreferred is orthofluoro as this appears to allow a favourable hydrogenbonding interaction with the hydroxy group on the adjacent indanol asdepicted in the representative compound denoted IVB′ below:

Exemplary compounds within Formula IVB thus include:

-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5    R)-2,5-di(benzyloxy)-3-hydroxy-4(L-valyloxy-(1-methyl)-methyloxy)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy4-O-(4-(L-valyloxy)butyryl)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy4-O-(4-(L-valyloxy)-cis-but-2-enoyl)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy4-O-(2-(L-valyloxymethyl)benzoyl)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-(L-valyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-(L-valyloxy-(1-methyl)-methyloxy)    hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3    R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(3-(L-valyloxy)propionyl)    hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)butyryl)hexanediamide,-   N1,N6di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(5-(L-valyloxy)pentanoyl)    hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(4-(L-valyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(2-(L-valyloxymethyl)benzoyl)    hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-(L-isoleucyloxy-(1-methyl)-methyloxy)    hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(3-(L-isoleucyloxy)propionyl)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(5-(L-isoleucyloxy)pentanoyl)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3-hydroxy-4-O-(2-(L-isoleucyloxy    methyl)benzoyl) hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-(L-isoleucyloxymethyloxy)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-(L-isoleucyloxy-(1-methyl)-methyloxy)hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(3-(L-isoleucylaxy)propionyl)    hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)butyryl)    hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(5-(L-isoleucyloxy)pentanoyl)    hexanediamide.-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy-4-O-(4-(L-isoleucyloxy)-cis-but-2-enoyl)    hexanediamide,-   N1,N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3-hydroxy4-O-(2-(L-isoleucyloxymethyl)benzoyl)    hexanediamide.

A still further aspect of the invention provides derivatives of theformula IVC, which compounds are alternative derivatives of the mothercompounds of formula IVB:

where X, Y, R_(z′), and R_(z″) are as defined above, one of R_(xc′) orR_(x″c″) is —O-L-R_(d′) and the other is OH or —O-L-R_(d″) and theposition adjacent the asterisk is occupied by —CH— or —N— therebydefining a fused cyclopentanylphenyl or pyridyl ring

Exemplary compounds within this aspect of the invention include:

-   N1,N6-di[(1S,2R)-2-(L-valyloxymethyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(L-valyloxy-(1-methyl)methyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(3-(L-valyloxy)propionyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(4-(L-valyloxy)butyryl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(5-(L-valyloxy)pentanoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(4(L-valyloxy)-cis-but-2-enoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(2-(L-valyloxymethyl)benzoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(L-isoleucyloxymethyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(L-isoleucyloxy-(1-methyl)methyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(3-(L-isoleucyloxy)propionyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(4-(L-isoleucyloxy)butyryl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(5-(L-isoleucyloxy)pentanoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(4-(L-isoleucyloxy)-cis-but-2-enoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(2-(L-isoleucyloxymethyl)benzoyl)-2,3-dihydro-1H-1-indeny    -(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(L-valyloxymethyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(L-valyloxy-(1-methyl)methyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4dihydroxy-hexanediamide,-   N1,N6-di[(1S    ,2R)-2-(3-(L-valyloxy)propionyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(4-(L-valyloxy)butyryl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(5-(L-valyloxy)pentanoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(4-(L-valyloxy)-cis-but-2-enoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(2-(L-valyloxymethyl)benzoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(L-isoleucyloxymethyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(L-isoleucyloxy-(1-methyl)methyloxy)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(3-(L-isoleucyloxy)propionyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(4-(L-isoleucyloxy)butyryl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,-   N1.N6-di[(1S,2R)-2-(5L-isoleucyloxy)pentanoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(4-(L-isoleucyloxy)-cis-but-2-enoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,-   N1,N6-di[(1S,2R)-2-(2-(L-isoleucyloxymethyl)benzoyl)-2,3-dihydro-1H-1-indenyl]-(2R,3R,4R,5R)-2,5-di(2-fluorobenzyloxy)-3,4-dihydroxy-hexanediamide,

A further aspect of the invention provides compounds wherein A′ and A″differ, preferably by including an amino terminus as depicted in FormulaIVA (including the isobutyl variant) and an amino terminus as depictedin Form IVB or IVC below. Methodology for preparing such asymmetricmother compounds is disclosed in PCT/SE98/00622. Representativeasymmetric compounds include those of the formula IVbb below:

where where X, Y, R_(z′), and R_(z″) are as defined above, one ofR_(xc′) or R_(x″c″) is —O-L-R_(d′) and the other is OH or —O-L-R_(d″)R_(aa) is H or CH₃ and the position adjacent the asterisk is occupied by—CH— or —N— thereby defining a fused cyclopentanylphenyl or pyridylring.

Favoured mother compounds of formula IVbb include those where R_(z) andR_(z′) are a cyclic group such as phenyl, pyridyl or the thiazolyl withthe formula:

The compounds of formula IVbb (as with indinavir above) have chainhydroxy functions amenable to the invention, but more importantly alsohave an easily accessible ring hydroxy function on the indanol.

In keeping with the usual practice with retroviral inhibitors it isadvantageous to co-administer one to three or more additionalantivirals, such as AZT, ddI, ddC, d4T, 3TC, H2G, foscarnet, ritonavir,indinavir, saquinavir, nevirapine, delaviridine, efavirenz, amprenavir,Agouron AG1343 and the like. Such additional antivirals will normally beadministered at dosages relative to each other which broadly reflecttheir respective therapeutic values. Molar ratios of 100:1 to 1:100,especially 25:1 to 1:25, relative to the compound or salt of formula Iwill often be convenient.

The compounds of the aspect of the invention discussed immediately aboveinvention are generally prepared by alkylation or acylation of therespective mother compounds, which are in turn prepared by themethodology described in PCT/SE98/00622. Alkylation or acylationgenerally proceeds via an activated derivative. The activated derivativeused in an acylation may comprise e.g, the acid halide, acid anhydride,activated acid ester or the acid in the presence of coupling reagent,for example dicyclohexylcarbodiimide, where “acid” to a precursor groupsuch as those of the formula PGNHC(R₁)COO-Lα—COOH, where R_(d) isdefined above, PG is a conventional N-protecting group and L_(α) is theresidue of the linker.

Activated L-R_(y) groups wherein L is derived from an hydroxyalkanoicacid are conveniently prepared by esterification of conventionallycarboxy protected hydroxyalkanoic acid, such as glycollic acid or lacticacid or more preferably an ω-hydroxyalkanoic acid such as3-hydroxypropionic acid, 4-hydroxybutyric acid, 5-hydroxypentanoic acidetc with the appropriate N-protected R_(y) derivative, such asN-Cbz-isoleucine, either as the free acid in conjunction with a couplingagent such as DCC, or activated, for instance to the corresponding acidhalide. The carboxy protecting group is removed as is known in the artand the resulting intermediate activated and esterified with the mothercompound of formula IV, such as those of formula IVA, IVB or IVC withthe methodology described above. The N-protecting group on R_(y) is thenremoved by conventional deprotection conditions.

Activated L-R_(y) groups wherein L is derived from a cis-alkenoic acid,such as 4-hydroxy-cis-but-2-en are conveniently prepared from thecorresponding haloalkanoic acids, such as 4-bromo-cis-but-2-enoic acidwhich is carboxy protected, for instance with t-butyl prior toconventional esterification under with the appropriately N-protectedR_(y) moiety, sicha N-Cbz-valine. The carboxy protecting group isremoved and the free carboxy activated and esterified with the mothercompound of formula IV as described above, followed by deprotection ofthe N-protecting group.

Activated L-R_(y) groups wherein L is derived from a2-hydroxymethylbenzoic acid can be prepared from 2-methylbenzoic acidwhich is carboxy protected and brominated by conventional techniques.This activated intermediate is esterified with an appropriatelyN-protected R_(y) moiety, such as Cbz-valine. This intermediate iscarboxy deprotected and esterified with the mother compound of formulaIV as described above, followed by deprotection of the R_(y)N-protecting group.

The term “N-protecting group” or “N-protected” as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undesirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in Greene, “Protective Groups in Organic Synthesis” (JohnWiley & Sons, New York, 1981), which is hereby incorporated byreference. N-protecting groups include acyl groups such as formyl,acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl,2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl,o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl, and the like, carbamate forminggroups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like. FavouredN-protecting groups include formyl, acetyl, allyl, F-moc, benzoyl,pivaloyl, t-butylacctyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC)and benzyloxycarbonyl (Cbz).

Hydroxy and/or carboxy protecting groups are also extensively reviewedin Greene ibid and include ethers such as methyl, substituted methylethers such as methoxymethyl, methylthiomethyl, benzyloxymethyl,t-butoxymethyl, 2-methoxyethoxymethyl and the like, silyl ethers such astrimethylsilyl (TMS), t-butyldimethysilyl (TBDMS) tribenzylsilyl,triphenylsilyl, t-butyldiphenylsilyl trisopropyl silyl and the like,substituted ethyl ethers such as 1-ethoxymethyl,1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl,dipehenylmethyl, tiiphenylmethyl and the like, aralkyl groups such astrityl, and pixyl (9-hydroxy-9-phenylxanthene derivatives, especiallythe chloride). Ester hydroxy protecting groups include esters such asformate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate,pivaloate, adamantoate, mesitoate, benzoate and the like. Carbonatehydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyland the like.

Useful intermediates for acylation with the mother compounds thusinclude: 3-N-Boc-L-valyloxypropanoic acid, 3-N-Fmoc-L-valyloxypropanoicacid, 3-N-CBZ-L-valyloxypropanoic acid, 3-N-Boc-L-isoleucyloxypropanoicacid, 3-N-Fmoc-L-isoleucyloxypropanoic acid,3-N-CBZ-L-isoleucyloxypropanoic acid, 4-N-Boc-L-valyloxybutyric acid,3-N-Fmoc-L-valyloxybutyric acid, 4-N-CBZ-L-valyloxybutyric acid,4-N-Boc-L-isoleucyloxybutyric acid, 3-N-Fmoc-L-isoleucyloxybutyric acid,3-N-CBZ-L-isoleucyloxybutyric acid and the like; and the activatedderivatives, such as the acid halides

Still further ueful intermediates include precursors, such as;2-(L-valyloxy)propanoic acid, 2-(N-Boc-L-valyloxy)propanoic acid,2-(N-Fmoc-L-valyloxy)propanoic acid, 2-(N-CBZ-L-valyloxy)propanoic acid,2-(L-isoleucyloxy)propanoic acid, 2-(N-Boc-L-isoleucyloxy)propanoicacid, N-(Fmoc-L-isoleucyloxy)propanoic acid,N-(CBZ-L-isoleucyloxy)propanoic acid, 2-(L-valyloxy)butyric acid,2-(N-Boc-L-valyloxy)butyric acid, 2-(N-Fmoc-L-valyloxy)butyric acid,2-(N-CBZ-L-valyloxy)butyric acid, 2-(L-isoleucyloxy)butyric acid,2-(N-Boc-L-isoleucyloxy)butyric acid, N-(Fmoc-L-isoleucyloxy)butyricacid, N-(CBZ-L-isoleucyloxy)butyric acid, and the like; and activatedderivatives therof, such as the acid halides.

Still further novel intermediates include precursors such as:

-   3-ethoxycarbonyl-2-valyloxy-propionic acid-   3-ethoxycarbonyl-2-isoleucyloxy-propionic acid-   4-ethoxycarbonyl-2,3-bis-valyloxy-butyric acid-   4-ethoxycarbonyl-2,3-bis-isoleucyloxy-butyric acid-   3-benzyloxycarbonyl-2-valyloxy-propionic acid-   3-benzyloxycarbonyl-2-isoleucyloxy-propionic acid-   4-benzyloxycarbonyl-2,3-bis-valyloxy-butyric acid-   4-benzyloxycarbonyl-2,3-bis-isoleucyloxy-butyric acid, and the like;    particularly those derived from “natural” configurations such as    L-malic and L-tartaric acid, and the corresponding activated    derivatives such as the acid halides.

Alkylation of the mother compound of figure IV, for instance when groupL-R_(y) is derived from an alkoxyamino acid ester, is conveniently donewith the corresponding N-protected haloalkoxyamino acid ester.Convenient alkylation intermediates thus include

-   iodomethyloxy-N-CBz-valyl,-   iodomethyloxy-N-Boc-valyl,-   iodomethyloxy-N-Fmoc-valyl-   iodomethyloxy-N-CBz-isoeucyl,-   iodomethyloxy-N-Boc-isoleucyl,-   iodomethyloxy-N-Fmoc-isoleucyl,    and corresponding derivatives bearing other N-protecting groups.

Further useful intermediates and methodology for acylation or alkylationof the mother compounds of formula IV are disclosed or suggested in(M132) SE 980216-4 filed 7 Apr. 1998, the contents of which arespecifically incorporated by reference.

Preparation of compounds of the formula IVB will generally require theindanolic hydroxy groups to be protected with conventional hydroxyprotecting groups prior to esterification or alkylation of the 3 and/or4 hydroxy groups of the alkyl backbone of the mother compound. On theother hand, the differential reactivity of the indanolic hydroxy groupsmeans that the compounds of the formula IVC can generally be preparedwithout corresponding protection of the 3 and 4 hydroxy groups.

Preparation of compounds of the formula IVA and IVB may requirerelatively stringent esterification/alkylaton conditions, thusfavouring, for instance, esterification with haloactivated L-R_(y)groups, as described above, rather than the use of a coupling agent.

A further useful group of compounds for applying the compounds of theinvention are the phenolic hydroxy compounds of the PETT series of NNRTIdisclosed in WO 93/03022, WO95/06034 and PCT/SE99/00053, the contents ofwhich are incorporated by reference. Favoured ring hydroxy compounds ofthis class have the formula P1:

where one of Rp1-3 is hydroxy and the others are hydrogen, halo, C₁₋₆alkanoyl, C₁₋₆ alkyl, C₁₋₆ alkoxy etc as defined in WO95/06034, Rp4 andRp5 are hydrogen or join to form a cis-cyclopropyl or cyclobutyl group,Rp6 is O or S and Rp7 is halo, cyano, amino etc as defined inWO95/06034. Particularly preferred compounds of this class have theformula P2:

wherein

-   Rp8 is halo;-   Rp9 is C₁-C₃ alkyl;-   Rp10 is halo, especially bromo or cyano.

A preferred subset of compounds within Formula P2, particularly withregard to pharmacokinetics, has Rp10 as cyano. A further favoured subsetof compounds within Formula P2, particularly with regard to ease offorming prodrugs, comprise compounds wherein Rp10 is bromo.

Preferably Rp8 is chloro and more preferably fluoro. Suitable Rp9 groupsinclude methyl, isopropyl, n-propyl and preferably ethyl.

As depicted in Formula P2, the cyclopropyl ring is in the cisconfiguration, allowing two enantiomers, 1S, 2S and 1R, 2R

Each of these enantiomers are potent antiretrovirals, although thedifferent enantiomers can display subtle differences in physiologicalproperties. For instance the 1S, 2S and 1R, 2R enantiomers can show adifferent pattern of metabolism within the P450 system. The 1S, 2Senantiomer of compounds wherein Rp10 is cyano is particularly preferredas it appears unique in being able to avoid key components of the P450system. Other retroviral agents such as the HIV protease inhibitorritonavir interact extensively with the P450 system, leading to an arrayof undesirable physiological responses including extensive alteration ofthe metabolism of other co-administered drugs. This is of particularconcern with pharmaceuticals administered for a chronic infection wherepatients can expect to take a number of pharmaceuticals for years, ifnot decades.

Preferred NNRTI mother compounds for applying the prodrugs of theinvention thus include:

-   (1S, 2S)-N-[cis-2-(6-fluoro, 2-hydroxy,    3-propionylphenyl)-cyclopropyl]-N′-(5-cyanopyrid-2-yl)-urea,-   (1S, 2S)-N-[cis-2-(6-fluoro, 2-hydroxy,    3-butyrylphenyl)-cyclopropyl]-N′-(5-cyanopyrid-2-yl)-urea,-   (1S, 2S)-N-[cis-2-(6-fluoro, 2-hydroxy,    3-acetylphenyl)-cyclopropyl]-N′-(5-cyanopyrid-2-yl)-urea,-   (1S, 2S)-N-[cis-2-(6-fluoro, 2-hydroxy,    3-propionylphenyl)-cyclopropyl]-N′-(5-bromopyrid-2-yl)-urea,-   (1S, 2S)-N-[cis-2-(6-fluoro, 2-hydroxy,    3-butyrylphenyl)-cyclopropyl]-N′-(5-bromopyrid-2-yl)-urea,-   (1S, 2S)-N-[cis-2-(6-fluoro, 2-hydroxy,    3-acetylphenyl)-cyclopropyl]-N′-(5-bromopyrid-2-yl)-urea,    and the corresponding R, R enantiomers.

This aspect of the invention thus provides prodrugs of NNRTI compoundsof the formula P-1, especially P-2 wherein the phenolic hydroxy functionis bonded to any of the generic structures above, such as those depictedin formula IIa, IIb, IIc, IId, IIe, IIf, Id, etc. These compounds areprepared by acylation of the relevant mother compound of formula P-1 orP-2 with the activated structure IIa, IIb etc, wherein the or each R₂group is conventionally N-protected.

As the compounds of formula P2 include an electron withdrawing group onthe phenol ring to which the prodrug moiety is attached it is generallypreferred to avoid direct esters such as 4-valyloxybutyric acidderivatives which are otherwise effective on phenols and carbocyclicring hydroxy functions.

Thus a convenient group of prodrugs within the scope of this aspect ofthe invention include those of the formula P3:

wherein

-   Rp8, Rp9, Rp10, R², R₄ and R_(4′) are as defined above. Typically    both of R₄ and R_(4′) are H.

Preferred compounds within Formula P3 include;

-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(L-valyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1R,    2R)-N-{cis-2-[6-fluoro-2-(L-valyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1R,    2R)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(L-valyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1R,    2R)-N-{cis-2-[6-fluoro-2-(L-valyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1R,    2R)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,    and pharmaceutically acceptable salts thereof.

An alternative preferred group of prodrugs of the invention have theFormula P4:

where Rp8, Rp9, Rp10, R₄ and R_(4′) are as defined above. L and R₂define a linker group and residue of an aliphatic amino acid, such asthose of Formulae IIa, IIb, IIc, IId, IIe, IIf or those depicted inFormulae Ia and Id. Typically both of R₄ and R_(4′) are H.

Favoured compounds within the class described in the immediatelypreceding paragraph include those of the formula P5:

where Rp8 Rp9, Rp10, R₄, R_(4′) and R₂ are as defined above and Alk^(b)is C₁-C₆ optionally branched, optionally monounsaturated alkyl.

Favoured compounds within Formula P5 thus include:

-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2-methyl-3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionyliphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2-methyl-3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(3-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2-methyl-3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-bromopyridyl)]urea-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2-methyl-3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(3-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(4-(L-valyloxy)-butyryl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(4-(L-isoleucyloxy)-butyryl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(4-(L-valyloxy)-butyryl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(4-(L-isoleucyloxy)-butyryl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2-(L-valyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-bromopyridyl)]urea,-   (1S,    2S)-N-{cis-2-[6-fluoro-2-(2-(L-isoleucyloxy)-propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl})-N′-[2-(5-bromopyridyl)]urea,    and the corresponding (1R, 2R) enantiomers thereof.

One variant of a branched Alk^(b) in Formula P5 can be substituted withhydroxy which in turn is esterified with a further R², thus defining alinker of the formula IIa, as depicted in Formula P6:

where Rp8, Rp9, Rp10, Alk, R₄, R₄′, m, n and R₂ are as defined above.Preferably each occurrence of Rx and Rx′ is H. Particularly favouredvalues for Alk, m and n include: methylene: 1:1 and absent: 1:0respectively.

A further favoured group of compounds has the Formula P7:

where Rp8, Rp9, Pp10, Alk, R₄, R₄′, m, n and R₂ are as defined above orwherein the -( )_(m)-O—R₂ arm is absent. Preferably each occurrence ofRx and Rx′ is H. Particularly favoured values for Alk, m and ninclude:absent:1:1, thus defining a glycerol derivative. Where the -()_(m)-O—R₂ arm is absent to define a structure of the formula P7′:

Convenient values for Alk and n include absent:1 with R₄, R₄ and R₄′ asH.

Favoured compounds within Formula P-7 thus include

-   (1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-L-valyloxy-2-(oxycarbonylmethoxy)propyl)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-L-isoleucyloxy-2-(oxycarbonylmethoxy)    propyl)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-L-valyloxy-2-(oxycarbonylmethoxy)propyl)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-bromopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-L-isoleucyloxy-2-(oxycarbonylmethoxy)    propyl)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-bromopyridyl)]urea,-   (1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-valyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)]    urea,-   (1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-isoleucyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)]    urea,-   (1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-valyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-bromopyridyl)]    urea,-   (1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-isoleucyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-bromocyanopyridyl)]    urea,    and the corresponding R,R enantiomers.

A further favoured group of compounds omit the methyloxy groupimmediately adjacent the ring hydroxy function of the compound offormula P1 or P2. An example of such compounds has the formula P8:

where Rp8, Rp9, Rp10, R₂, and Alk^(b) are as defined above. Currentlyfavoured values for Alk include methylene, ethylene,1,1-dimethylethylene, propylene, butylene and, in the case of said —OR₂substitution, glycerol.

Favoured compounds within formula P-8 thus include:

-   (1S,2S)-N-[cis-2-(6-fluoro-2-(L-valyloxymethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(L-isoleucyloxymethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(L-valyloxymethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-bromopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(L-isoleucyloxymethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-bromopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(2-(L-valyloxy)ethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(2-(L-isoleucyloxy)ethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(2-(L-valyloxy)ethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-bromopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(2-L-isoleucyloxy)ethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-bromopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(3-(L-valyloxy)propoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(3-(L-isoleucyloxy)propoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea,-   (1    S,2S)-N-[cis-2-(6-fluoro-2-(3-(L-valyloxy)propoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-bromopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(3-(L-isoleucyloxy)propoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-bromopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(4-(L-valyloxy)butoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(4-(L-isoleucyloxy)butoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(4-(L-valyloxy)butoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-bromopyridyl)]urea,-   (1S,2S)-N-[cis-2-(6-fluoro-2-(4-(L-isoleucyloxy)butoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-bromopyridyl)]urea,    and the corresponding R, R enantiomers

As with Formula P5/P6 and P7/P7′, Alk^(b) in formula P8 can comprise anadditional —O—R₂ substitution to define a compound of the formula P8′

where each of the variables is as defined above.

This Formulae P aspect of the invention further provides pharmaceuticalcompositions comprising the compounds of formula and pharmaceuticallyacceptable carriers or diluents therefor. Additional aspects of theinvention provide methods for the inhibition of HIV comprisingadministering a compound of the formula I to a subject afflicted withHIV. The invention also extends to the use of the compounds of formula Iin therapy, such as in the preparation of a medicament for the treatmentof HIV infections.

In treating conditions caused by HIV, the compounds of formula I arepreferably administered in an amount to achieve a plasma level of thecompounds of Formula P1 of around 10 to 1000 nM and more preferably 100to 500 nM. This corresponds to a dosage rate, depending on thebioavailability of the formulation, of the order 0.01 to 10 mg/kg/day,preferably 0.1 to 2 mg/kg/day. A typical dosage rate for a normal adultwill be around 0.05 to 5 g per day, preferably 0.1 to 2 g such as500-750 mg, in one to four dosage units per day.

In keeping with the usual practice with HIV inhibitors it isadvantageous to co-administer one to three additional antivirals toprovide synergistic responses and to ensure complementary resistancepatterns. Such additional antivirals may include AZT, ddI, ddC, D4T,3TC, abacavir, adefovir, adefovir dipivoxil, bis-POC-PMPA, foscarnet,hydroxyurea, Hoechst-Bayer HBY 097, efavirenz, trovirdine, nevirapine,delaviridine, PFA, H2G, ABT 606, DMP-450, loviride, ritonavir,saquinavir, indinavir, amprenavir (Vertex VX 478), nelfinavir and thelike, typically at molar ratios reflecting their respective activitiesand bioavailabilities. Generally such ratio will be of the order of 25:1to 1:25, relative to the compound of formula I.

Compounds of this Formulae P aspect of the invention are typicallyprepared by alkylation of the corresponding mother compounds of FormulaP1 or especially P2, which are prepared by conventional means, such asthe methodology described in WO95/06034 or PCT/SE99/00053. Inparticular, the preparation of compounds of formula P-3 or P-4 generallyproceeds by alkylation using conventional coupling conditions of acompound of the formula P-2 with the corresponding intermediate:

where Rx and L are as defined above and R₂* is R₂ as defined, butN-protected with a conventional N-protecting group. Preferably thehalogen activating group is iodo, which is in turn prepared byiodination of the corresponding chloro analogue. Typical couplingconditions include treatment with a base in an organic solvent such asTHF prior to addition of the halogenated intermediate followed byconventional deprotection of the R₂ N-protecting group.

Compounds of formula P-8 are generally prepared by esterification of acompound of the formula P-2 with an intermediate of the formula:

where Alk^(b)* is a functionalised Alk^(b) as described above, forexample chloromethyl chloroformate, in an organic solvent, followed byiodination of the terminal chloro with NaI (or other activation of thefunctionalising group) and reaction with an N-protected R₂.

The compounds of the invention can form salts which form an additionalaspect of the invention. Appropriate pharmaceutically acceptable saltsof the compounds of Formula I include salts of organic acids, especiallycarboxylic acids, including but not limited to acetate,trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate,malate, pantothenate, isethionate, adipate, alginate, aspartate,benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate,glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate,palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate,tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate,organic sulphonic acids such as methanesulphonate, ethanesulphonate,2-hydroxyethane sulphonate, camphorsulphonate, 2-napthalenesulphonate,benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate;and inorganic acids such as hydrochloride, hydrobromide, hydroiodide,sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoricand sulphonic acids. The compounds of the invention I may be isolated asthe hydrate.

While it is possible for the active agent to be administered alone, itis preferable to present it as part of a pharmaceutical formulation.Such a formulation will comprise the above defined active agent togetherwith one or more acceptable carriers or excipients and optionally othertherapeutic ingredients. The carrier(s) must be acceptable in the senseof being compatible with the other ingredients of the formulation andnot deleterious to the recipient.

The formulations include those suitable for rectal, nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous and intradermal)administration, but preferably the formulation is an orally administeredformulation. The formulations may conveniently be presented in unitdosage form, e.g. tablets and sustained release capsules, and may beprepared by any methods well known in the art of pharmacy.

Such methods include the step of bringing into association the abovedefined active agent with the carrier. In general, the formulations areprepared by uniformly and intimately bringing into association theactive agent with liquid carriers or finely divided solid carriers orboth, and then if necessary shaping the product. The invention extendsto methods for preparing a pharmacutical composition comprising bringinga compound of Formula I or its pharmaceutically acceptable salt inconjunction or association with a pharmaceutically acceptable carier orvehicle. If the manufacture of pharmaceutical formulations involvesintimate mixing of pharmaceutical excipients and the active ingredientin salt form, then it is often preferred to use excipients which arenon-basic in nature, i.e. either acidic or neutral.

Formulations for oral administration in the present invention may bepresented as discrete units such as capsules, cachets or tablets eachcontaining a predetermined amount of the active agent; as a powder orgranules; as a solution or a suspension of the active agent in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water in oil liquid emulsion and as a bolus etc.

With regard to compositions for oral administration (e.g. tablets andcapsules), the term suitable carrier includes vehicles such as commonexcipients e.g. binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose,ethylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers,for example corn starch, gelatin, lactose, sucrose, microcrystallinecellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride andalginic acid; and lubricants such as magnesium stearate, sodium stearateand other metallic stearates, stearic acid, glycerol stearate, siliconefluid, talc waxes, oils and colloidal silica. Flavouring agents such aspeppermint, oil of wintergreen, cherry flavouring or the like can alsobe used. It may be desirable to add a colouring agent to make the dosageform readily identifiable. Tablets may also be coated by methods wellknown in the art.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active agent in a free flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, preservative, surface-active or dispersingagent. Moulded tablets may be made by moulding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.The tablets may be optionally be coated or scored and may be formulatedso as to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include lozengescomprising the active agent in a flavoured base, usually sucrose andacacia or tragacanth; pastilles comprising the active agent in an inertbase such as gelatin and glycerin, or sucrose and acacia; andmouthwashes comprising the active agent in a suitable liquid carrier.

A still further aspect of the invention provides novel R₂ bearinglinkers suitable for derivatisation to free functions on a Drug.Preferred linkers in accordance with this aspect of the inventioninclude compounds of the Formulae IVa:

where R₂, A, A′, n, m, Q, Alk, k and T are as defined above and R₄ ishydroxy or an activating group such as an acid derivatives including theacid halide, such as the chloride, anhydrides derived fromalkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like,N-hydroxysuccinamide derived esters, N-hydroxyphthalimide derivedesters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters,2,4,5-trichlorophenol derived esters and the like. Compounds of FormulaIVa will be particularly useful for Drugs bearing hydroxy or aminefunctions.

Further preferred linkers in accordance with this aspect of theinvention include compounds of the formulae IVe:

where R₂, A, A′, n, m, Q, Alk and T are as defined above, and R₄ anactivating group such as a halide, including bromo, chloro and iodo.Compounds of Formula IVe will be especially useful for Drugs bearingcarboxy functions (especially those where T is O, R₃ is Me and R₃′ is H)or phosphonyl functions (especially those where T is a bond, R₃ isisopropyl and R₃′ is H).

Alternative preferred di- or trifunctional linker compounds of thisaspect of the invention include compounds of the Formulae IIIa:

where R₂, A, A′, n, m, Q and Alk are as defined above and R₄ is hydroxyor an activating moiety such as halo, including chloro, iodo and bromo.

In practice linker compounds of Formula IVa or the correspondingderivative of Formula II′a will be esterified to hydroxy-bearing Drugsusing conventional acylation techniques. The activated moiety of FormulaIV may be preformed or generated in situ by the use of reagents such asdicyclohexylcarbodiimide (DCC) or O—(1H-benotriazol-1-yl)N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU). When an acidhalide, such as the acid chloride is used, a tertiary amine catalyst,such as triethylamine, N,N′-dimethylaniline, pyridine ordimethylaminopyridine may be added to the reaction mixture to bind theliberated hydrohalic acid.

The reactions are preferably carried out in an unreactive solvent suchas N,N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile or ahalogenated hydrocarbon, such as dichloromethane. If desired, any of theabove mentioned tertiary amine catalysts may be used as solvent, takingcare that a suitable excess is present. The reaction temperature cantypically be varied between −20° C. and 60° C., but will preferably bekept between 5° and 50° C. After a period of 1 to 60 hours the reactionwill usually be essentially complete. The progress of the reaction canbe followed using thin layer chromatography (TLC) and appropriatesolvent systems. In general, when the reaction is completed asdetermined by TLC, the product is extracted with an organic solvent andpurified by chromatography and/or recrystallisation from an appropriatesolvent system.

By-products where acylation has taken place on an inappropriate functioncan be separated by chromatography, but such misacylation can beminimized by controlled reaction conditions. These controlled conditionscan be achieved, for example, by manipulating the reagent concentrationsor rate of addition, especially of the acylating agent, by lowering thetemperature or by the choice of solvent. The reaction can be followed byTLC to monitor the controlled conditions. It may additionally oralternatively be convenient to protect exposed hydroxy and otherfunctions on the Drug with conventional protecting groups to forestallmisacylation.

Linkers of Formula IVa or the corresponding derivatives of Formula II′amay alternatively be amide bonded to free primary or secondary aminefunctions on the Drug using conventional chemistry in the peptide art.

Linkers of Formula IIIa or IVd or the corresponding derivatives ofFormula III′ and II′d will generally be acylated to free carboxylfunctions on the Drug in an analogous, but reversed fashion to the abovedescribed acylation of Drugs with hydroxy functions. U.S. Pat. No.4,486,425 which is incorporated by reference illustrates a convenientprocess.

Linkers of Formula IVa wherein V comprises a structure of the formulaIIc can be prepared by a by a two stage process. In particular acompound of the formula ClC(═O)OC(R₄)(R₄′)Cl can be reacted with asuitable accessible hydroxy function on the Drug (optionally protectedon other functions with conventional protecting groups) as is known inthe cephalosporin art. The resulting Drug-O—C(═O)OC(R₄)(R₄′)chloride isthen reacted with an R₂ bearing linker wherein a free function comprisesa carboxyl function, such as the potassium salt.

Linkers of Formula IVe or the corresponding derivatives of Formula IIecan be esterified to phosphonyl and phosphoryl functions of Drugsanalogously to the processes shown in U.S. Pat. No. 4,337,201 and U.S.Pat. No. 5,227,506, which are incorporated by reference. Correspondingmenthodology is applicable when R₂ is esterified to a phosphonyl orphosphoryl group via a spacer of the Formula IIb as defined above.

The preparation of further linker groups and their application to Drugsis shown in the following Examples.

As the Drugs envisaged in the use of the present invention are provenpharmaceuticals, the starting materials for preparing the prodrugs ofthe invention are either available in commerce or are extensivelydescribed in the medical literature, including the FDA and otherregistration files for the respective drugs.

The term “N-protecting group” or “N-protected” as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undesirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in Greene, “Protective Groups in Organic Synthesis” (JohnWiley & Sons, New York, 1981), which is hereby incorporated byreference. N-protecting groups include acyl groups such as formyl,acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl,2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl,o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl, and the like, carbamate forminggroups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and thelike; alkyl gropus such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like. FavouredN-protecting groups include formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) andbenzyloxycarbonyl (Cbz).

Hydroxy and/or carboxy protecting groups are also extensively reviewedin Greene ibid and include ethers such as methyl, substituted methylethers such as methoxymethyl, methylthiomethyl, benzyloxymethyl,t-butoxymethyl, 2-methoxyethoxymethyl and the like, silyl ethers such astriethylsilyl (TMS), t-butyidimethylsilyl (TBDMS) tribenzylsilyl,triphenylsilyl, t-butyldiphenylsilyl triisopropyl silyl and the like,substituted ethyl ethers such as 1-ethoxymethyl,1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl,dipehenylmethyl, triphenylmethyl and the like, aralkyl groups such astrityl, and pixyl (9-hydroxy-9-phenylxanthene derivatives, especiallythe chloride). Ester hydroxy protecting groups include esters such asformate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate,pivaloate, adamantoate, mesitoate, benzoate and the like. Carbonatehydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyland the like.

“Optional substituents” can include hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkanoyl, amino, halo, cyano, azido,oxo, mercapto and nitro, and the like. “Ring” as used herein includesatoms including monocyclic rings such as furyl thienyl, pyranyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, isothiazolidinyl, and the like or bicyclicrings especially of the above fused to a phenyl ring such as indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl,benzothienyl etc. The carbo or heterocyclic ring may be bonded via acarbon to the remainder of the linker via a hetero atom, typically anitrogen atom, such as N-piperidyl, N-morpholinyl etc.

DETAILED DESCRIPTION BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of the invention will now be described by way of exampleonly with reference to the following Examples and the accompanyingdrawings in which;

FIG. 1 depicts serum viral-DNA levels in treated and untreated,DHBV-infected ducks as a function of time, as described in BiologicalExample 3;

FIG. 2 depicts weight gain in treated, DHBV-infected ducks as a functionof time, as described in Biological Example 3.

PREPARATION OF INTERMEDIATES EXAMPLE P-I-1 N-BOC-L-isoleucine iodomethylester

a) N-BOC-L-isoleucine chloromethyl ester

To a solution of N-BOC-L-isoleucine (23.1 g, 0.1 mol) in dioxane (500mL), was added dropwise a 40% aqueous solution of tetrabutylammoniumhydroxide (65.6 mL, 0.1 mol). After stirring for 15 min, the solutionwas evaporated to dryness through co-evaporation with dioxane andtoluene. The residue was dissolved in dichloromethane (500 mL) and thenchloroiodomethane (72.8 mL, 1 mol) was added and the solution wasstirred for 6 h at room temperature. The solution was concentrated underreduced pressure and the residue was shaken with hexane/ethyl acetate(1:1 v/v, 400 mL). The yellow crystalline solid was filtered off and thefiltrate was washed with aqueous solution of sodium thiosulfate (0.1 M)and then filtered through anhydrous sodium sulfate and evaporated todryness. The residue was column chromatographed (silica gel, 1-2% MeOHin CH₂Cl₂), to give 20.8 g of N-BOC-L-isoleucine chloromethyl ester.

¹H-NMR (CDCl₃): 5.86 (d, 1H), 5.60 (d, 1H), 5.04 (d, 1H), 4.32-4.25 (m,1H), 2.00-1.80 (m, 1H), 1.42 (s, 9H), 1.50-1.05 (m, 2H), 0.96-0.87 (m,6H).

b) N-BOC-L-isoleucine iodomethyl ester

To a solution of N-BOC-L-isoleucine chloromethyl ester (19.6 g, 70 mmol)in acetonitrile (300 mL), was added sodium iodide (31.5 g, 210 mmol).The solution was stirred for 4 h at 60° C. The resulting suspension wasfiltered and the filtrate was evaporated. The residue was dissolved inCH₂Cl₂ and washed with aqueous sodium thiosulfate (0.1 M). The organicphase was dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude product was column chromatographed (silica gel, 2% MeOH inCH₂Cl₂), to give 22.6 g of N-BOC-L-isoleucine iodomethyl ester.

¹H-NMR (CDCl₃): 6.04 (d, 1H), 5.82 (d, 1H), 4.97 (d, 1H), 4.25 (dd, 1H),1.98-1.80 (m, 1H), 1.43 (s, 9H), 1.50-1.05 (m, 2H), 0.97-0.88 (m, 6H).

EXAMPLE PI-2 2.2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid iodomethylester

a) 2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid:

N-Boc-L-valine (10.8 g, 50 mmole), 4-dimethylaminopyridine (610 mg, 5mmole) and DCC (6.18 g, 30 mmole) were dissolved in methylene chloride(100 ml). After stirring for 2 hour the mixture was filtered. To thefiltrate were added 2,2-dimethyl-3-hydroxy-propionic acid (3.54 g, 30mmole) and pyridine (10 ml). After 18 hr, the reaction mixture wasfiltered, and the filtrate was poured into sodium hydrogen carbonateaqueous solution, the organic phase was then washed with citric acidaqueous solution and water succesively. After evaporation the productwas isolated with silica gel column chromatography to yield 4.4 g. Thiscompound can be activated and esterified directly to a drug or furthermodified as described below.

¹H-NMR (CDCl₃): 5.10 (d, 1H) 4.24 (m, 3H) 2.18 (m, 1H) 1.51 (s, 9H) 1.33(d, 6H) 0.98 (m, 6H).

b) 2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid chloromethyl ester

2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid (3.9 g, 12.3 mmole) wasdissolved in dioxane (60 ml). To the solution was addedtetrabutylammonium hydroxide aqueous solution (40%, 7.78 ml, 12 mmole).The solution was dried in vacuo, and it was coevaporated with toluenefor several times. The residue was dissolved in methylene chloride andthen chloroiodomethane (18.9 ml, 260 mmole) was added to the solution.After 18 hr, the reaction solution was evaporated and the product wasisolated with silica gel column chromatography to yield 3.7 g.

¹H-NMR (CDCl₃): 5.72 (s, 2H) 5.00 (d, 1H) 4.20 (m, 3H) 2.12 (m, 1H) 1.44(s, 9H) 1.25 (d, 6H) 0.91(m, 6H)

c) 2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid iodomethyl ester

2,2-Dimethyl-3-(N-Boc-L-valyloxy)propionic acid chloromethyl ester (3.6g, 10 mmole) was dissolved in acetonitrile (50 ml). Sodium iodide (2.1g, 14 mmole) was added to the solution. After reaction at 70° C. for 2hr, the reaction mixture was filtered and the residue was dissolved inmethylene chloride (20 ml) and refiltered. The solution was dried andgave 4.34 g of the titled product.

¹H-NMR (CDCl₃): 5.92 (dd, 2H) 5.10 (d, 1H) 4.24 (m, 1H) 4.15 (dd, 2H)2.01 (m, 1H) 1.44 (s, 9H) 1.25 (d, 6H) 0.91 (m, 6H)

EXAMPLE P-I-3 3,3-bis (N-CBz-L-valyloxymethyl)-propionic acid iodomethylester

a) Preparation of 3,3-bis (N-CBz-L-valyloxymethyl)-propionic acidchloromethyl ester

3,3-bis (N-CBz-L-valyloxymethyl)-propionic acid (3 g, 5 mmole) wasdissolved in dioxane (20 ml). To the solution was addedtetrabutylammonium hydroxide aqueous solution (40%, 3.11 ml, 4.8 mmole).The solution was dried in vacuo, and it was coevaporated with tolueneseveral times. The residue was dissolved in methylene chloride (15 ml)and then chloroiodomethane (7.3 ml, 100 mmole) was added to thesolution. The reaction solution was refluxed for 18 hr and thenevaporated and the product was isolated with silica gel columnchromatography. 900 mg.

¹H-NMR (CDCl₃): 7.33 (m, 10 H) 5.68 (dd, 2H) 5.26 (d, 2H) 4.25 (m, 6H)2.56 (m, 1H) 2.48 (d, 2H) 2.14 (m, 2H) 0.93 (m, 12 H)

b) 3,3-bis-(N-CBz-L-valyloxymethyl)propionic acid iodomethyl ester

3,3-bis (N-CBz-L-valyloxymethyl)-propionic acid chloromethyl ester (900mg, 1.38 mmole) was dissolved in acetonitrile (5 ml). Sodium iodide (289mg, 1.93 mmole) was added to the solution. After reaction at 70° C. for3 hr, the reaction mixture was filtered and the residue was dissolved inmethylene chloride (5 ml) and refiltered. The solution was dried andgave the titled product. 800 mg.

¹H-NMR (CDCl₃): 7.35 (m, 10 H) 5.88 (dd, 2H) 5.25 (d, 2H) 4.29 (m, 2H)4.18 (m, 4H) 2.56 (m, 1H) 2.42 (d, 2H) 2.16 (m, 2H) 0.93 (m 12 H)

EXAMPLE P-I-4 2-N-CBz-L-valyloxy)ethoxycarbonyloxymethyl iodide

2-(N-CBz-L-valyloxy)ethoxycarbonyloxymethyl chloride (1.16 g, 3 mmole)was dissolved in acetonitrile (10 ml). Sodium iodide (630 g, 4.2 mmole)was added to the solution. After reaction at 65° C. for 2.5 hr, thereaction mixture was cooled down to room temperature and filtered andthe residue was dissolved in methylene chloride (5 ml) and refiltered.The solution was dried and gave the titled product. 1.2 g.

¹H-NMR (CDCl₃): 7.35 (m, 5H) 5.93 (dd, 2H) 5.26 (d, 1H) 5.11 (s, 2H)4.39 (m, 5H) 2.18 (m, 1H) 0.94 (m, 6H).

EXAMPLE P-I-5 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyliodomethyl carbonate)

a) 1-O-(N-tert-butoxycarbonyl-L-valyl)glycerol

N-tert-Butoxycarbonyl-L-valine (32.53 g, 0.150 mol),N,N′-dicyclohexyl-carbodiimide (37.85 g, 0.183 mol, and4-dimethylaminopyridine (1.83 g, 0.015 mol) were added to glycerol(138.12 g., 1.5 mol) in 500 mL dry DMF and the mixture was stirred at rtunder N₂ for 3 days. The reaction mixture was filtered, concentratedunder vacuum, and then partitioned between 300 mL EtOAc and 150 mL H₂O.The aqueous phase was reextracted with 150 mL EtOAc. The organic phaseswere combined and washed successively with 100 mL each of saturatedaqueous NaHCO₃, saturated NH₄Cl, and brine. Drying over anhydrousNa₂SO4, and concentration under vacuum gave a viscous light yellow oilas crude product. Flash column chromatography on silica gel with 4/1EtOAc—petroleum ether (BP 40-60° C.) gave 18.27 g (42%) of product(alternative nomenclature:3-(N-tert-butoxycarbonyl-L-valyloxy)-1,2-propanediol). Reactions doneovernight gave similar yields.

¹H NMR (250 MHz, CDCl₃) δ 0.91 (d, 3H), 0.97 (d, 3H), 1.43 (s, 9H), 2.12(m, 1H), 3.54-3.74 (m, 2H), 3.94 (m, 1H), 4.09-4.32 (m, 3H), 5.09 (br s,1H).

b) 1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)glycerol

1-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (17.95 g. 61.6 mmol),Boc-L-valine (6.69 g, 30.8 mmol), DMAP (0.38 g, 3.1 mmol), and DCC (7.10g, 34.4 mmol) in 240 mL CH₂Cl₂ and 60 mL DMF were stirred at rt under N₂for 18 h. The reaction mixture was filtered, concentrated under vacuum,and redissolved in 200 mL EtOAc. The organic solution was washed with 50mL saturated NH₄Cl. The aqueous phase was reextracted with 50 mL EtOAc.The organic phases were combined, washed successively with 50 mLsaturated NaHCO₃ and 50 mL brine, dried over NA₂SO₄ and concentratedunder vacuum. Flash column chromatography of the crude material onsilica gel (eluent 2/1 petroleum ether-EtOAc, and then EtOAc) gave 7.41g (49%) of the title compound (alternative nomenclature:1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propanol).

¹H NMR (CDCl₃) δ 0.90 (d, 6H), 0.97 (d, 6H), 1.43 (s, 18H), 2.12 (m,2H), 4.06-4.30 (m, 7H), 5.04 (br d, 2H).

c)2-O-chloromethoxycarbonyl-1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)glycerol

Chloromethyl chloroformate (2.70 mL, 30 mmol) was added to a solution of1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)glycerol (7.27 g, 14.8 mmol) andpyridine (7.2 mL, 89 mmol) in 60 mL dry CH₂Cl₂, in an ice bath, underN₂. After stirring for 1 h 45 min, the reaction mixture was diluted with100 mL CH₂Cl₂ and washed with 40 mL water. The aqueous phase wasreextracted with 20 mL H₂O. The organic phases were combined, washedwith 40 mL saturated NaHCO₃, followed by 2×50 mL brine, dried overNa₂SO₄, and concentrated under vacuum. Flash column chromatography onsilica gel with 2/1 hexane-EtOAc gave 8.03 g (93%) of the title compound(alternative nomenclature:1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl chloromethylcarbonate).

¹H NMR (250 MHz, CDCl₃) δ 0.84 (d, 6H), 0.92 (m, 6H), 1.39 (s, 18H),2.08 (m, 2H), 4.15-4.50 (m, 6H), 4.99 (br d, 2H), 5.16 (m, 1H), 5.69 (s,2H).

d)2-O-iodomethoxycarbonyl-1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)glycerol

A solution of2-O-chloromethoxycarbonyl-1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)propane-1,2,3-triol(7.86 g, 13.5 mmol) and NaI (8.09 g, 54.0 mmol) in 135 mL dryacatonitirile was refluxed at 80° C. for 4 h under N₂. The reactionmixture was concentrated under vacuum, and then partitioned between 150mL diethyl ether and 50 mL H₂O. The aqueous layer was reextracted with2×25 mL ether. The combined organic phases were washed successively with25 mL aqueous Na₂S₂O₃ and 50 mL brine, dried over NA₂SO₄, andconcentrated. Flash column chromatography (silica gel, 2/1 hexane-ethylacetate gave 8.38 g (92%) title product (alternative name:2-iodomethoxycarbonyloxy-1,3-bis-(N-tert-butoxycarbonyl-L-valyloxy)propaneor 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl iodomethylcarbonate) as a white solid.

¹H NMR (250 MHz, CDCl₃) δ 0.81 (d, 6H), 0.88 (m, 6H), 1.36 (s, 18H),2.06 (m, 2H), 4.11-4.46 (m, 6H), 5.0 (br d, 2H), 5.12 (m, 1H), 5.88 (s,2 H).

EXAMPLE G-I-1 2,3-Bis-(N-CBz-L-valyloxy)-propionic acid

a) t-Butyl 2,3-bis (N-CBz-L-valyloxy)propionate.

To a solution of t-butyl 2,3-dihydroxypropionate (2.43 g, 15 mmole),N-CBz-L-valine (7.54 g, 30 mmole) and DMAP (0.37 g, 3 mmole) in 150 mldichloromethane was added DCC (7.2 g 35 mmole) and the mixture wasstirred for two days at room temperature. The mixture was cooled toabout 5° C. and the urethane was filtered. The filtrate was evaporated,ethyl acetate was added and the organic phase washed twice with 5%acetic acid, 5% sodium hydrogen carbonate and water. The organic phasewas dried with sodium sulfate filtered and evaporated under reducedpressure. The product was isolated by silica gel column chromatography.Yield: 8.2 g=86%

¹H-NMR (DMSO d-6) 0.87 (m, 12H) 1.40 (d, 9H) 2.12 (m, 1H) 4.02-4.40 (m,2H) 5.04 (d, 4H) 5.20 (m 1H) 7.36 (m, 10H) 7.72 (d, 2H)

b) 2,3-Bis -N-CBz-L-valyloxy)-propionic acid.

To a solution of t-butyl -2,3-bis-(N-CBz-L-valyloxy)-propionate (7.2 g,11.4 mmole) in dichloromethane (25 ml) was added tifluoroacetic acid (25ml) and the solution was stirred for five hours at room temperature. Thesolution was evaporated under reduced pressure and coevaporated twotimes with toluene. The product was isolated by silica gel columnchromatography. Yield: 5.9 g=90%

¹H-NMR (DMSO-d6) 0.92 (m, 12H) 2.08 (m, 2H) 3.92-4.17 (m, 2H) 4.30-4.67(m, 2H) 5.04 (s, 4H) 5.28 (m, 1H) 7.32 (m, 10H) 7.70 (m, 2H)

EXAMPLE G-I-2 (S)-(+)-2-(N-CBz-L-valyloxy)propionic acid

a) 4-Methoxybenzyl (S) (+)-2-hydroxypropionate.

To a stirred solution of (S)(+)2 hydroxypropionic acid (9.0 g, 100mmole) in 100 ml dry DMF was added potassium tert-butoxide (12.34 g, 110mmole) and the mixture was stirred for one hour at 25° C.,4-Methoxybenzyl chloride (18.8 g 120 mmole) was added and the mixturewas stirred for six hours at 60° C. The mixture was evaporated underreduced pressure and 250 ml ethyl acatate was added. The organic phasewas washed four times with water. The organic phase was dried withsodium sulfate and concentrated in vacuo. Yield: 15.6 g=74%

¹H-NMR (CDCl₃) 1.40 (d, 3H) 3.81 (s, 3H) 4.26 (m, 1H) 5.14 (s, 2H) 6.90(d, 2H) 7.28 (d, 2H)

b) 4-Methoxybenzyl (S)-(+)-2-(N-CBz-L-valyloxy)propionate.

To a solution of 4-methoxybenzyl (S)-(+)-2-hydroxypropionate (7.6 g, 36mmole), N-CBZ-L-valine (10.05 g, 40 mmole) and DMAP (0.98 g, 8 mmole) in150 ml dichloromethane was added a solution of DCC (8.3 g, 40 mmole) andthe mixture was stirred overnight at room temperature. The mixture wascooled to about 5° C. and the urethane was filtered. The filtrate wasevaporated and the product was isolated by silica gel columnchromatography. Yield: 14.4 g=90%

¹H-NMR (CDCl₃) 0.94 (m, 6M) 1.50 (d, 3H) 2.26 (m, 1H) 3.81 (s, 3H) 4.34(d, d, 1H) 5.10-5.25 (m, 6H) 6.88 (d, 2H) 7.26 (m, 7H)

c) (S)-(+)-2-(N-CBz-L-valyloxy)propionic acid.

To a solution of 4-methoxybenzyl (S)-(+)-2-(N-CBz-L-valyloxy)propionate(14.0 g, 31.5 mmole) in dichloromethane (50 ml) was addedtrifluoroacetic acid (25 ml) and the solution was stirred for five hoursat room temperature. The solution was evaporated under reduced pressureand coevaporated two times with toluene. The product was isolated bysilica gel column chromatography. Yield: 9.4 g=92%

¹H-NMR (DMSO-d6) 0.94 (m, 6H) 1.46 (d, 3H) 2.12 (m, 1H) 4.05 (m, 1H)4.92 (m, 1H) 5.06 (s, 2H) 7.34 (m, 5H) 7.68 (d, 1H)

EXAMPLE F-I-3 3,3-Bis(N-CBz-L-valyloxymethyl)-propionic acid

a) 4,4-bis (N-CBZ-L-valyloxymethyl)-but-1-ene.

To a solution of 2-allyl-1,3-propanediol (2.32 g, 20 mmole),N-CBZ-L-valine (10.06 g, 40 mmole) and DMAP (0.488 g, 4 mmole) in 120 mldichloromethane was added DCC (9.08 g, 44 mmole) in portions and themixture was stirred overnight at room temperature. The mixture wascooled to 5° C. and the urethane was filtered. The filtrate wasevaporated and the product was isolated by silica gel columnchromatography. Yield: 9.0 g

¹H-NMR (CDCl₃) 0.89 (m, 12H) 5.11 (s, 2H) 5.73 (m, 1H)

b) 3,3-Bis (N-CBZ-L-valyloxymethyl)-propionic acid.

To a cooled solution of 4,4-bis (N-CBZ-L-valyloxymethyl)-but-1-ene (14.6g, 25 mmole) and tetrabutylammonium bromide (1.3 g, 4 mmole) in 120 mlbenzene was added 100 ml water. Under strong stirring potassiumpermanganate (15.8 g, 100 mmole) was addded in portions and the mixturewas stirred for 2 hours between 15° C. and 20° C. A sodium bisulfiteaqueous solution was added to the slurry until the mixture wasdiscolored. The mixture was acidified with 2N hydrochloric acid andextracted four times with ethyl acetate. The organic phase was washedtwo times with water, dried with sodium sulfate and evaporated underreduced pressure. The product was isolated by silica gel columnchromatography. Yield: 7.5 g

¹H-NMR (CDCl₃) 0.89 (m, 12H) 2.05 (m, 2H) 2.46 (m, 2H) 2.62 (m, 1H) 4.20(m, 6H) 5.11 (s, 4H) 5.30 (m, 2H) 7.35 (m, 10H)

EXAMPLE F-I-4 2-(N-CBZ-L-valyloxy)-propionic acid

a) 4-methoxybenzyl 2-hydroxypropionate.

To a stirred solution of DL-2 hydroxypropionic acid (9.0 g, 100 mmole)in 100 ml dry DMF was added potassium tert-butoxide (12.34 g, 110 mmole)and the mixture was stirred for one hour at 60° C. 4-methoxybenzylchloride (18.8 g 120 mmole) was added and the mixture was stirred foreight hours at 60° C. The mixture was evaporated under reduced pressureand 250 ml ethyl acatate was added. The organic phase was washed fourtimes with water. The organic phase was dried with sodium sulfate andconcentrated in vacuo. Yield: 16.8 g

¹H-NMR (CDCl₃) 1.40 (m, 3H) 3.81 (s, 3H) 4.26 (m, 1H) 5.14 (s, 2H) 6.90(d, 2H) 7,28 (d, 2H)

b) 4-methoxybenzyl 2-(N-CBZ-L-valyloxy)propionate.

To a solution of 4-methoxybenzyl 2-hydroxypropionate (4.2 g, 20 mmole),N-CBZ-L -valine (5.02 g, 20 mmole) and DMAP (0.24 g, 2 mmole) in 100 mldichloromethane was added a solution of DCC (4.54 g, 22 mmole) and themixture was stirred overnight at room temperature. The mixture wascooled to 5° C. and the urethane was filtered. The filtrate wasevaporated and the product was isolated by silica gel columnchromatography. Yield: 7.9 g

¹H-NMR (CDCl₃) 0.88 (m, 6H) 1.50 (m, 3H) 2.26 (m, 1H) 3.81 (s, 3H) 4.34(m, 1H) 5.04-5.30 (m, 6H) 6.88 (d, 2H) 7.26 (m, 7H)

c) 2-(N-CBZ-L-valyloxy)-propionic acid.

To a solution of 4-methoxybenzyl 2-(N-CBZ-L-valyloxy)-propionate (7.8 g,17.5 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid(10 ml) and the solution was stirred for one hour at room temperature.The solution was evaporated under reduced pressure and the product wasisolated by silica gel column chromatography. Yield: 5.0 g

¹H-NMR (CDCl₃) 0.94 (m, 6H) 1.56 (d, 3H) 2.30 (m, 1H) 4.42 (m, 1H)5.12-5.30 (m, 4H) 7.28 (m, 5H)

EXAMPLE F-I-5 Succinic acid 2,3-bis-(N-CBZ-L-valyloxy)propyl ester

a) 4-Methoxybenzyl succinate monoester.

To a mixture of succinic anhyride (75 g, 750 mmole) and 4-methoxybenzylalcohol (69.1 g, 500 mmole) in 1,4-dioxane (300 ml) was added pyridine(79.1 g, 1000 mmole) and the mixture was stirred for five hours at 80°C. The mixture was evaporated under reduced pressure and 600 ml of ethylacetate and 60 ml of acetic acid were added. The organic phase waswashed three times with water, dried with sodium sulfate and evaporatedunder reduced pressure. The product was recrystallized from toluene.Yield: 104 g.

¹H-NMR (DMSO d-6) 2.48 (m, 4H) 3,72 (s, 3H) 5.00 (s, 2H) 6.90 (d, 2H)7.28 (d, 2H)

b) Succinic acid 2,3-dihydroxy-propyl ester, 4-methoxybenzyl ester.

To a solution of glycerol (23.0 g, 250 mmole), 4methoxybenzyl succinatemonoester (5.96 g, 25 mmole) and DMAP (0.36 g, 3 mmole) in DMF (200 ml)was added DCC (6.2 g 30 mmole) and the mixture was stirred overnight atroom temperature. The mixture was evaporated under reduced pressure and150 ml dichloromethane was added. The mixture was filtered and thesolution washed twice with water. The water phase was extracted twotimes with dichloromethane and the combined organic phases were driedwith sodium sulfate. The solution was evaporated under reduced pressureand the product was isolated by silica gel column chromatography. Yield:3.0 g

¹H-NMR (CDCl₃) 2.65 (m, 4H) 3.61 (m, 2H) 3.80 (s, 3H) 3.90 (m, 1H) 4.18(m, 2H) 5.05 (s, 2H) 6.89 (d, 2H) 7.26 (d, 2H)

c) Succinic acid 2,3-bis-(N-CBZ-L-valyloxy)-propyl ester,4-methoxybenzyl ester.

To a stirred solution of succinic acid 2,3-dihydroxy-propyl ester,4-methoxybenzyl ester (2.9 g, 9.28 mmole), N-CBZ-L-valine (5.03 g, 20mmole) and DMAP (0.244 g, 2 mmole) in dichloromethane (60 ml) was addedDCC (4.5 g, 22 mmole) and the mixture was stirred overnight at roomtemperature. The mixture was filtered and the solution was evaporatedunder reduced pressure. The product was isolated by silica gel columnchromatography. Yield: 2.5 g

¹H-NMR (CDCl₃) 0.90 (m, 12H) 2,16 (m, 2H) 2.62 (m, 4H) 3.80 (s, 3H) 4.32(m, 4H) 5.05-5.52 (m, 9H) 6.89 (d, 2H) 7.30 (m, 12H)

d) Succinic acid 2,3-bis-(N-CBZ-L-valyloxy)propyl ester.

To a solution of the above intermediate (2.3 g, 2.95 mmole) indichloromethane (25 ml) was added trifluoroacetic acid (2.5 ml) and thesolution was stirred for two hours at room temperature. The solution wasevaporated under reduced pressure and the product was isolated by silicagel column chromatography. Yield: 1,8 g

¹H-NMR (CDCl₃) 0.92 (m, 12H) 2.12 (m, 2H) 2.64 (m, 4H) 4.32 (m, 4H) 5.10(s, 4H) 5.22-5.50 (m, 3H) 7.34 (m, 10H)

EXAMPLE F-I-6 Succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester

a) Succinic acid 1,3-dibromo-2-propyl ester, 4-methoxybenzyl ester.

To a solution of 1,3-dibromopropan-2-ol (21.8 g, 100 mmole), succinicacid 4-methoxybenzyl ester (28.6 g, 120 mmole) and DMAP (1.22 g, 10mmole) in dichloromethane (400 ml) was added DCC (24.8 g, 120 mmole) inportions at about 10° C. The mixture was stirred overnight at roomtemperature and cooled to about 5° C. The mixture was filtered and thesolution was evaporated under reduced pressure. 600 ml of ethyl acetatewas added and the organic phase was washed twice with 5% acetic acid, 5%sodium hydrogen carbonate and water. The solution was dried with sodiumsulfate and evaporated under reduced pressure. The product was isolatedby silica gel column chromatography. Yield: 34.8 g.

¹H-NMR (CDCl₃) 2.69 (m, 4H) 3.57 (m, 4H) 3.81 (s, 3H) 5.07 (s, 2H) 5.14(m, 1H) 6,88 (d, 2H) 7.26 (d, 2H)

b) Succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester,4-methoxybenzyl ester.

To a solution of N-CBZ-L-valine (58.5 g, 232.8 mmole) in dried DMF (300ml) was added potassium-tert.-butoxide (24,68 g, 220 mmole) and themixture was stirred for one hour at room temperature. A solution ofsuccinic acid 1,3-dibromo-2-propyl ester, 4-methoxybenzyl ester (34 g,77.6 mmole) in dried DMF (50 ml) was added and the mixture was stirredfor eighteen hours at 60° C. The potassium bromide was filtered and thesolution was evaporated under reduced pressure. 600 ml of ethyl acetatewas added and the organic phase washed twice with 5% sodium hydrogencarbonate and with water. The organic phase was dried with sodiumsulfate and evaporated under reduced pressure. The product was isolatedby silica gel column chromatogaphy. Yield: 45 g

¹H-NMR (CDCl₃) 0.90 (m, 12H) 2.16 (m, 2H) 2.61 (m, 4H) 3.80 (s, 3H )4.12-4.42 (m, 6H) 5.02 (s, 2H) 5.10 (s, 4H) 5.43 (m, 3H) 6.88 (d, 2H)7.32 (m, 12H)

c) Succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester.

To a cooled solution of the intermediate immediately above (44.5 g, 57.1mmole) in dichloromethane (500 ml) was added trifluoroacetic acid (50ml) between 5° C. and 10° C. and the solution was stirred for two hoursat 10° C. The solution was evaporated under reduced pressure and twotimes coevaporated with toluene. 400 ml of ethanol was added and themixture was stirred for 30 minutes at 40° C. The mixture was cooled andthe biproduct filtered. The solution was evaporated under reducedpressure and the product was isolated by silica gel columnchromatography. Yield: 33 g

¹H-NMR (DMSO-d6) 0.88 (m, 12H) 2.04 (m, 2H) 2.46 (m, 4H) 3.94-4.40 (m,6H) 5.02 (s, 4H) 5.18 (m, 1H) 7.32 (m, 10H) 7,74 (d, 2H)

EXAMPLE F-I-7 Alternative Route to succinic acid1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester

a) Succinic acid 1,3-dibromo-2-propyl ester, 1,1-dimethylethyl ester.

To a solution of 1,3-dibromopropan-2-ol (10.9 g 50 mmole), succinic acid1,1-dimethylethyl ester (J. Org. Chem 59 (1994) 4864) (10.45 g, 60mmole) and DMAP (0.61 g, 5 mmole) in dichloromethane (180 ml) was addedDCC (12.4 g, 60 mmole) in portions at about 10° C. The mixture wasstirred overnight at room temperature and cooled to about 5° C. Themixture was filtered and the solution was evaporated under reducedpressure. 250 ml ethyl acetate was added and the organic phase waswashed twice with 5% citric acid, 5% sodium hydrogen carbonate andwater. The solution was dried with sodium sulfate and evaporated underreduced pressure. The product was distilled in vacuo. (bp 0,5 135-140°C.) Yield; 16.8 g

¹H-NMR (CDCl₃) 1.45 (s, 9H) 2.58 (m, 4H) 3.61 (m, 4H) 5.12 (m, 1H)

b) Succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester,1,1-dimethylethyl ester.

To a solution of N-CBZ-L-valine (18.85 g, 75 mmole) in dried DMF (100ml) was added potassium tert.-butoxide (7.85 g, 70 mmole) and themixture was stirred for one hour at room temperature. A solution ofsuccinic acid 1,3-dibromo-2-propyl ester, 1,1-dimethylethyl ester (9.35g, 25 mmole) in dried DMF (20 ml) was added and the mixture was stirredfor eighteen hours at 60° C. The potassium bromide was filtered and thesolution evaporated under reduced pressure. 300 ml of ethyl acetate wereadded and the organic phase washed twice with 5% sodium hydrogencarbonate and with water. The organic phase was dried with sodiumsulfate and evaporated under reduced pressure. The product was isolatedby silica gel column chromatography. Yield: 14 g

¹H-NMR (CDCl₃) 0.90 (m, 12H) 1.42 (s, 9H) 2.14 (m, 2H) 2.52 (m, 4H) 4.32(m, 6H) 5.10 (s, 4H) 5.32 (m, 3H) 7.26 (m, 10H)

c) 1,3-bis-(N-CBZ-L-valyloxy )-2-propyl succinate monoester.

To a cooled solution of succinic acid1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester, 1,1-dimethylethyl ester (13g, 18.18 mmole) in dichloromethane (100 ml) was added trifluoroaceticacid (20 ml) and the solution was stirred for six hours at roomtemperature. The solution was evaporated under reduced pressure. 200 mlethyl acetate was added and the organic phase was washed with 5% sodiumhydrogen carbonate and water. The solution was evaporated under reducedpressure. Yield: 11.7 g

¹H-NMR (DMSO-d6) 0.88 (m, 12H) 2.04 (m, 2H) 2.46 (m, 4H) 3.94-4.40 (m,6H) 5.02 (s, 4H) 5.18 (m, 1H) 7.32 (m, 10H) 7.74 (d, 2H)

EXAMPLE P-I-6 3-benzyloxycarbonylpropionic acid chloromethyl ester

a) Succinic acid monobenzyl ester

Succinic anhydride (30 g, 300 mmole) was dissolved in methylene chloride(300 ml). To the solution were added benzyl alcohol (10.2 ml, 100mmole), 4-dimethylaminopyridine (1.22 g, 10 mmole) and pyridine (48 ml).After 3 hours the reaction mixture was poured in to citric acid aqueoussolution. The organic phase was concentrated to small volume and sodiumhydrogen carbonate and water were added. Then mixture was stirred for 30min. The aqueous phase was collected, and to it was added citric acidaqueous solution. The product precipitated out, was collected and dried.15.3 g.

¹H-NMR (CDCl₃): 7.50 (m, 5H), 5.25 (s, 2H), 2.68 (m, 4H).

b) 3-benzyloxycarbonylpropionic acid chloromethyl ester

Succinic acid monobenzyl ester (4.16 g, 20 mmole) was dissolved indioxane (20 ml). To the solution was added tetrabutylammonium hydroxideaqueous solution (40%, 11.6 ml, 18 mmole). The solution was dried invacuo and coevaporated with toluene several times. The residue wasdissolved in methylene chloride (60 ml) and then chloroiodomethane (14.5ml, 200 mmole) was added to the solution. The reaction solution wasstirred for 18 hr and then evaporated and the product was isolated withsilica gel column chromatography. 3.64 g

¹H-NMR (CDCl₃): 7.35 (m, 5H), 5.67 (s, 2H), 5.13 (s, 2H), 2.72 (s, 4H).

c) 3-Benzyloxycarbonylpropionic acid iodomethyl ester

3-Benzyloxycarbonylpropionic acid chloromethyl ester (2 g, 1.38 mmole)was dissolved in acetonitrile (30 ml). Sodium iodide (1.6 g, 10.9 mmole)was added to the solution. After reaction at 70° C. for 3 hr, thereaction mixture was filtered and the residue was dissolved in methylenechloride (20 ml) and refiltered. The solution was dried and gaveintermediate 3-benzyloxycarbonylpropionic acid iodomethyl ester inquantitative yield. This intermediate is bonded to an accessiblefunction of a drug, such as a ring hydroxy or carboxy function usingconventional alkylation/acylation conditions as described generallyherein. Following deprotection of the terminal carboxy, adi/trifunctional linker bearing R₂, such as 1,3-bis-O-(L-valyl)glycerolor iodomethyloxy-L-valyl is acylated/alkylated thereon or R₂ amidebonded thereon by conventional techniques as described herein, such aswith DCC coupling agent.

EXAMPLE B-I-1 4-(N-Boc-L-valyloxy)butyric acid

a) Preparation of 4-bromobutyric acid benzyl ester

4-bromobutyric acid (10.6 g, 60 mmole) was dissolved in thionyl chloride(20 mml), and the reaction was kept for 4 hr. The solution wasevaporated and coevaporated. with toluene several times. The residue wasredissolved in dichloromethane (120 ml), and then benzyl alcohol (4.14ml, 40 mmole) was added. The solution was cooled down to −50° C. andtriethylamine (10 ml, 72 mmole) was added. The reaction mixture wasslowly warmed to room temperature. After 3 hr, the reaction mixture waspoured into sodium bicarbonate aqueous solution and the organic phasewas washed with water and dried, giving the titled product, 6.8 g.

¹H-NMR (CDCl₃): 7.38 (m, 5H) 5.12 (m, 2 H) 3.46 (t, 2H) 2.57 (t, 2H)2.20 (m, 2H).

b) Preparation of 4-(N-Boc-L-valyloxy)butyric acid benzyl ester

N-Boc-L-valine (1.3 g, 6 mmole) was dissolved in dioxane (5 ml). To thesolution was added tetrabutylammonium hydroxide aqueous solution (40%,3.8 ml, 6 mmole), and the solution was evaporated and coevaporated withtoluene several times. The residue was dissolved in DMF (15 ml) and4-bromobutyric acid benzyl ester (1.28 g, 5 mmole) was added to it. Thereaction was kept for 18 hr, and then poured into sodium bicarbonateaqueous solution and extracted with dichlorometane. The organic phasewas dried and the product was isolated with silica gel columnchromatography, 1.2 g.

¹H-NMR (CDCl₃): 7.35 (m, 5H) 5.13 (m, 2 H) 5.00 (d, 1H) 4.28 (m, 3H),2.48 (t, 2H), 2.05 (m, 2H) 1.46 (s, 9 H) 0.93 (m, 6 H).

c) 4-(N-Boc-L-valyloxy)butyric acid

To a solution of 4-(N-Boc-L-valyloxy)butyric acid benzyl ester (1.2 g, 3mmole) in ethyl acetate/methanol (5 ml/5 ml) was added palladium black(20 mg). The reaction mixture was kept under hydrogen at atmosphericpressure for 2 hr. The suspension was filtered through Celite and dried,giving the title product, 840 mg.

¹H-NMR (CDCl₃): 5.05 (d, 1H) 4.20 (m, 3H) 2.48 (t, 2H) 2.00 (m, 2H) 1.46(s, 9H) 0.96 (m, 6H).

A-I-1 Iodomethyl2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionate

a) 4-Methoxybenzyl 2-(hydroxymethyl)-2-methyl propionate.

2-(Hydroxymethyl)-2-methyl propionic acid was esterified by alkylationwith 4-methoxybenzyl chloride by conventional means, namely treatmentwith aqueous NaOH, followed by evaporation and dissolution in an organicsolvent such as DMF to which the 4-methoxybenzyl chloride is added andthe reaction warmed and agitated, such as stirring at 60 C. for onehour. The reaction mixture is cooled, concentrated by rotavapor and theresulting concentrated suspension partitioned between water anddichloromethane. The organic phase is evaporated and the residesubjected to silica gel column chromatography, for example with 0, 2, 4%EtOH in dichlorometane to yield the title compound (7.10 g). R_(f)(2%/MeOH/CHCl₂) 0.40.

¹H-NMR (CDCl₃): 7.26 (d, 2H), 6.90 (d, 2H), 5,07 (s, 2H), 3.80 (s, 3H),3.55 (s, 2H), 2.44 (br, 1H), 1.19 (s, 6H).

b) 4-Methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methylpropionate.

4-Methoxybenzyl 2-(hydroxymethyl)-2-methyl propionate (2.50 g, 10.5mmol), N-benzyloxy carbonyl-L-valine (2.51 g, 10 mmole),4-dimethylaminopyridine (183 mg) and 1-hydroxybenzotriazole (1.35 g, 10mmole) were mixed and dissolved in N,N-dimethylformamide (90 ml). Thendicyclohexyl-carbodiimide (2.47 g 12 mmol) was added. After stirring for3 days at room temperature the suspension was filtered and the filtrateevaporated in vacuo. The residue was partitioned between 0.1M citricacid and dichloromethane. The organic phase was then extracted withaqueous saturated NaHCO₃ and evaporated in vacuo. The residue was silicagel column chromatographed (0, 1, 2, 3% ethanol in dichloromethane). Theappropriate fractions were pooled and evaporated in vacuo to give thetitle compound (2.72 g). R_(f) (2% MeOH/CHCl₃) 0.75.

¹H-NMR (CDCl₃): 7.36 (s, 5H), 7.26 (d, 2H), 6.88 (d, 2H), 5.22 (d, 1H),5.10 (s, 2H), 5.04 (s, 2H), 4.27 (d,d, 1H), 4.15 (d,d, 2H), 3.79 (s,3H), 2.05 (m, 1H), 1.23 (s, 3H), 1.20 (s, 3H), 0.91 (d, 3H), 0.81 (d,3H).

d) 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methyl propionic acid

To a solution of 4-methoxybenzyl2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methyl propionate (2.72 g,5.76 mmole), was added trifluoroacetic acid (11.5 ml) and the emergingdark red solution was stirred for 30 min at room temperature. Thesolution was evaporated to dryness with dioxane and toluene. The residuewas silica gel column chromatographed (2, 3, 4% ethanol indichloromethane). The appropriate fractions were pooled and evaporatedin vacuo to give the title compound (1.86 g). R_(f) (2% MeOH/CHCl₃)0.30.

¹H-NMR (CDCl₃): 7.32 (s, 5H), 5.32 (d, 1H), 5.10 (s, 2H), 4.32 (d,d,1H), 4.21 (d,d, 2H), 2.13 (m, 1H), 1.26 (s, 3H), 1.25 (s, 3H), 0.95 (d,3H), 0.86 (d, 3H).

c) Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methylpropionate

2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methyl propionic acid wasesterified by conventional techniques, namely dissolution in an organicsolvent such as dioxane and dropwise addition of aqueoustetrabutylammonium hydroxide, followed by evaporation. The residue isdissolved in dichloromethane and then chloroiodomethane and the mixturestirred for 6 hours at room temperature, followed by partition, shakingthe filtrate with aqueous sodium thiosulphate. 0.1M, filtration andevaporation. The title compound (1.40 g) was obtained after silica gelcolumn chromatography (0, 1, 2, 3% ethanol in dichloromethane). R_(f)(2% MeOH/CHCl₃) 0.80.

¹H-NMR (CDCl₃): 7.33 (s, 5H), 5.69 (s, 2H), 5.25 (d, 1H), 5.10 (s, 2H),4.30 (d,d, 1H), 4.16 (d,d, 2H), 2.14 (m, 1H), 1.27 (s, 3H), 1.25 (s,3H), 0.95 (d, 3H), 0.86 (d, 3H).

c) Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methylpropionate.

Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methylpropionate was converted to iodide by conventional techniques, namelyaddition to NaI in acetonitrile, stirring and heating, for instance to75 C. for four hours. The resulting suspension is filtered and thefiltrate evaporated, dissolved in organic solvent such as toluene andshaken with aqueous sodium thiosulphate (0.1M) and evaporation to givethe title compound (1.25 g) practically pure. R_(f) (2% MeOH/CHCl₃)0.80.

¹H-NMR (CDCl₃): 7.35 (s, 5H), 5.90 (d,d, 2H), 5.24 (d, 1H), 5.10 (s,2H), 4.31 (d,d, 1H), 4.14 (d,d, 2H), 2.16 (m 1H), 1.22 (s, 6H), 0.96 (d,3H), 0.87 (d, 3H).

EXAMPLE A-I-2 Iodomethyl2-(N-benzyloxycarbonyl-L-valyloxy)-DL-propionate.

a) Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-DL-propionate.

2-(N-benzyloxycarbonyl-L-valyloxy) propionic acid (1 g) was esterifiedby the method described in Example A-I-I, step d. The title compound(0.76 g) was obtained after silica gel column chromatography (0, 1%ethanol in dichloromethane). R_(f) (2% MeOH/CHCl₃) 0,75.

¹H-NMR (CDCl₃): 7.33 (s, 5H), 5.79 (d, 1H), 5.63 (d, 1H), 5.30 (d, 1H),5.14 (q, 1H), (q, 1H), 5.10 (s, 2H), 4.39 (d,d, 1H), 2.30 (m, 1H), 1.54(d, 3H), 1.03 (d, 3H), 0.95 (d, 3H).

b) Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-DL-propionate

Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-methylpropionate was converted to iodide by the method described in ExampleA-I-1, step e to give the title compound (0.95 g) practically pure.R_(f) (2% MeOH/CHCl₃) 0.75.

¹H-NMR (CDCl₃): 7.33 (s, 5H), 5.98 (d, 1H), 5.86 (d, 1H), 5.26 (d, 1H),5.10 (s, 2H), 5.07 (q, 1H), 4.38 (d,d, 1H), 2.30 (m, 1H), 1.49 (d, 3H),1.03 (d, 3H), 0.95 (d, 3H).

EXAMPLE A-I-3 Iodomethyl(1,3-di-(N-benzyloxycarbonyl)-L-valyloxy)-2-propyl carbonate

a) Chloromethyl (1,3-di-(N-benzyloxycarbonyl)-L-valyloxy)-2-propylcarbonate.

To a solution of 1,3-di-((N-benzyloxycarbonyl)-L-valyloxy)propan-2-ol(1.34 g, 2.4 mmole) in dichloromethane (10 ml) was added dry pyridine(1.15 ml, 14.4 mmol) and chloromethyl chloroformate (0.43 ml, 4.8 mmole)at 0° C. The reaction was then stirred for 30 min and then poured intoaqueous 50% saturated sodium chloride/0.1M citric acid solution andextracted with dichloromethane. The organic phase was evaporated and theresidue silica gel column chromatographed (0, 1, 1.5% ethanol indichloromethane). The appropriate fractions were pooled and evaporatedin vacuo to give the title compound (1.26 g). R_(f) (2% MeOH/CHCl₃)0.85.

¹H-NMR (CDCl₃): 7.34 (s, 10H), 5.68 (s, 2H), 5.21 (m, 3H), 5.10 (s, 4H),4.50-4.12 (m, 6H), 2.14 (m, 2H), 0.97 (d, 6H), 0.88 (d, 6H).

b) Preparation of Iodomethyl(1,3-di-(N-benzyloxycarbonyl)-L-valyloxy)-2-propyl carbonate.

Chloromethyl (1,3-di-(N-benzyloxycarbonyl)valyloxy)-2-propyl carbonatewas converted to iodide by the method described in Example A-I-1, stepe) to give the title compound (1.37 g) practically pure. R_(f) (2%MeOH/CHCl₃) 0.85.

¹H-NMR (CDCl₃): 7.34 (s, 10H), 5.93 (d, 1H), 5.89 (d, 1H), 5.21 (m, 3H),5.11 (s, 4H), 4.50-4.17 (m, 6H), 2.12 (m, 2H), 0.97 (d, 6H), 0.88 (d,6H).

EXAMPLE A-I-4 Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy)isobutyrate

a) 4-Methoxybenzyl 2-hydroxyisobutyrate.

2-hydroxy isobutyric acid (1.56 g) was esterfied by alkylation with4-methoxybenzyl chloride by the method described in Example A-I-1, stepa). The title compound (2.65 g) was obtained after silica gel columnchromatography (0, 1, 2% ethanol in dichloromethane). R_(f) (2%MeOH/CHCl₃) 0.45.

¹H-NMR (CDCl₃): 7.26 (d, 2H), 6.89 (d, 2H), 5.12 (s, 2H), 3.80 (s, 3H),3.17 (s, 1H), 1.42 (s, 6H).

b) 4-Methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyrate.4-methoxybenzyl 2-hydroxyisobutyrate was acylated withN-benzyloxycarbonyl-L-valine by the method described in Example A-I-1,step b). The title compound (3.21 g) was obtained after silica gelcolumn chromatography (0, 1, 1.5% ethanol in dichloromethane). R_(f) (2%MeOH/CHCl₃) 0.70.

¹H-NMR (CDCl₃): 7.33 (s, 5H), 7.26 (d, 2H), 6.88 (d, 2H), 5.22 (d, 1H),5.10 (2xs, 4H), 4.28 (d,d, 1H), 3.79 (s, 3H), 2.15 (m, 1H), 1.56 (s,3H), 1.54 (s, 3H), 0.95 (d, 3H), 0.84 (d, 3H).

c) 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyric acid.

4-methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyrate wasde-esterified by the method described in Example A-I-1 step c. The titlecompound (2.01 g) was obtained after silica gel column chromatography(2, 10, 20% ethanol in dichloromethane). R_(f) (2% MeOH/CHCl₃) 0.30.This compound may be activated and esterified directly to a drug, orfurther modified as described below.

¹H-NMR (CDCl₃): 7.32 (s, 5H), 5.33 (d, 1H), 5.10 (s, 2H), 4.31 (d,d,1H), 2.22 (m, 1H), 1.57 (s, 6H), 0.98 (d, 3H), 0.89 (d, 3H).

d) Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyrate.

2-(N-benzyloxycarbonyl-L-valyloxy) isobutyric acid was esterified by themethod described in Example A-I-1, step d. The title compound (1.90 g)was obtained after silica gel column chromatography (0, 1, 1.5% ethanolin dichloromethane). R_(f) (2% MeOH/CHCl₃) 0.80.

¹H-NMR (CDCl₃): 7.33 (s, 5H), 5.68 (s, 2H), 5.25 (d, 1H), 5.11 (s, 2H),4.30 (d,d, 1H), 2.21 (m, 1H), 1.59 (s, 3H), 1.57 (s, 3H), 1.00 (d, 3H),0.90 (d, 3H).

e) Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyrate.

Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy) isobutyrate wasconverted to iodide by the method described in Example A-I-1, step e togive the title compound (2.32 g) practically pure. R_(f) (2% MeOH/CHCl₃)0.80.

¹H-NMR (CDCl₃): 7.33 (s, 5H), 5.89 (s, 2H), 5.22 (d, 1H), 5.11 (s, 2H),4.29 (d,d, 1H), 2.21 (m, 1H), 1.55 (s, 3H), 1.53 (s, 3H), 1.00 (d, 3H),0.93 (d, 3H).

EXAMPLE A-I-5 Iodomethyl2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate

a) 4-Methoxybenzyl 2-hydroxy-3-methyl-(S)-(+)-butyrate.

2-hydroxy-3-methyl-(S)-(+)-butyric acid (1.77 g) was esterified byalkylation with 4-methoxybenzyl chloride by the method described inExample A-I-1, step a. The title compound (3.10 g) was obtained aftersilica gel column chromatography (0, 1, 2% ethanol in dichloromethane).R_(f) (2% MeOH/CHCl₃) 0.50.

¹H-NMR (CDCl₃): 7.27 (d, 2H), 6.90 (d, 2H), 5.19 (d, 1H), 5.12 (d, 1H),4.05 (d,d, 1H), 3.81 (s, 3H), 2.70 (d, 1H), 2.06 (heptet, 1H), 3.55 (s,2H), 0.98 (d, 3H), 0.80 (d, 3H).

b) 4-Methoxybenzyl2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate.

4-Methoxybenzyl 2-hydroxy-3-methyl-(S)-(+)-butyrate was acylated withN-benzyloxycarbonyl-L-valine by the method described in Example A-I-1,step b. The title compound (5.74 g) was obtained after silica gel columnchromatography (0, 1, 1.5% ethanol in dichloromethane). R_(f) (2%MeOH/CHCl₃) 0.70.

¹H-NMR (CDCl₃): 7.36 (s, 5H), 7.27 (d, 2H), 6.87 (d, 2H), 5.27 (d, 1H),5.10 (s, 4H), 4.88 (d, 1H), 4.40 (d,d, 1H), 3.80 (s, 3H), 2.25 (m, 2H),1.01-0.81 (m, 12H).

c) 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyric acid.

4-methoxybenzyl2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate wasde-esterified by the method described in Example A-I-1, step c. Thetitle compound (3.41 g) was obtained after silica gel columnchromatography (2, 10, 20% ethanol in dichloromethane). R_(f) (2%MeOH/CHCl₃) 0.45. The compound may be activated and esterified directlyto a drug or further modified as described below:

¹H-NMR (CDCl₃): 7.36 (s, 5H), 5.38 (d, 1H), 5.11 (s, 4H), 4.90 (d, 1H),4.41 (d,d, 1H), 2.28 (m, 2H), 1.04-0.89 (m, 12H).

d) Chloromethyl2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate.

2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyric acid wasesterified by the method described in Example A-I-1, step d. The titlecompound (2.96 g) was obtained after silica gel column chromatography(0, 1, 2% ethanol in dichloromethane). R_(f) (2% MeOH/CHCl₃) 0.85.

¹H-NMR (CDCl₃): 7.36 (s, 5H), 5.84 (d, 1H), 5.60 (d, 1H), 5.28 (d, 1H),5.11 (s, 4H), 4.88 (d, 1H), 4.42 (d,d, 1H), 2.30 (m, 2H), 1.05-0.90 (m,12H),

e) Iodomethyl2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate.

Chloromethyl2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate wasconverted to iodide by the method described in Example A-I-1, step e togive the title compound (3.64 g) practically pure. R_(f) (2% MeOH/CHCl₃)0.85.

¹H-NMR (CDCl₃): 7.36 (s, 5H), 6.00 (d, 1H), 5.83 (d, 1H), 5.28 (d, 1H),5.11 (s, 4H), 4.83 (d, 1H), 4.41 (d,d, 1H), 2.29 (m, 2H), 1.05-0.90 (m,12H).

EXAMPLE A-I-6 Iodomethyl2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate

a) 4-Methoxybenzyl 2-hydroxy-2-phenyl-DL-acetate.

DL-mandelic acid (2.28 g) was esterified by alkylation with4-methoxybenzyl chloride by the method described in Example A-I-1, stepa. The title compound (3.69 g) was obtained after silica gel columnchromatography (0, 1, 1.5% ethanol in dichloromethane). R_(f) (2%MeOH/CHCl₃) 0.55.

¹H-NMR (CDCl₃): 7.34 (m, 5H), 7.15 (d, 2H), 6.83 (d, 2H), 5.18 (d, 1H),5.15 (d, 1H), 5.03 (d, 1H), 3.78 (s, 3H), 3.48 (s, 1H).

b) 4-Methoxybenzyl2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate.

4-Methoxybenzyl 2-hydroxy-2-phenyl-DL-acetate was acylated withN-benzyloxycarbonyl-L-valine by the method described in Example A-I-1,step b. The title compound (6.50 g) was obtained after silica gel columnchromatography (0, 1, 1.5% ethanol in dichloromethane). R_(f) (2%MeOH/CHCl₃) 0.75.

¹H-NMR (CDCl₃): 7.36 (m, 10H), 7.14 (2xd, 2H), 6.81 (d, 2H), 5.95 (d,1H), 5.27 (m, 1H), 5.14-5.01 (m, 4H), 4.43 (m, 1H), 3.78 (s, 3H), 2.21(m, 1H), 1.03-0.82 (m, 6H).

c) 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetic acid.

4-Methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetatewas de-esterified by the method described in Example A-I-1, step c. Thetitle compound (4.75 g) was obtained after silica gel columnchromatography (2, 10, 20% ethanol in dichloromethane). R_(f) (2%MeOH/CHCl₃) 0.40. The compound may be activated and esterified directlyto a drug or further modified as described below.

¹H-NMR (CDCl₃): 7.36 (m, 10H:), 5.91 (d, 1H), 5.27 (m, 1H), 5.04 (s,2H), 4.57-4.40 (2xd,d, 1H), 2.30 (m, 1H), 1.01-0.82 (m, 6H).

d) Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate.

2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetic acid wasesterified by the method described in Example A-I-1, step d. The titlecompound (1.69 g) was obtained after silica gel column chromatography(0, 1, 2% ethanol in dichloromethane). R_(f) (2% MeOH/CHCl₃) 0.80.

¹H-NMR (CDCl₃): 7.36 (m, 10H), 5.98, 5.95 (2xs, 1H), 5.74-5.61 (m, 2H),5.32 (m, 1H), 5.10 (s, 2H), 4.43 (m, 1H), 2.30 (m, 1H), 1.07-0.5 (m,6H).

e) Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate.

Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxy)-2-phenyl-DL-acetate wasconverted to iodide by the method described in Example A-I-1, step e togive the title compound (1.89 g) practically pure. R_(f) (2% MeOH/CHCl₃)0.80.

¹H-NMR (CDCl₃): 7.36 (m, 10H), 5.94-5.82 (m, 3H), 5.28 (m, 1H), 5.10 (s,2H), 4.46 (m, 1H), 2.21 (m, 1H), 1.08-0.85 (m, 6H).

EXAMPLE A-I-7 Iodomethyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate

a) 4-Methoxybenzyl 4-hydroxybenzoate.

4-Hydroxybenzoic acid (1.38 g) was esterified by alkylation with4-methoxybenzyl chloride by the method described in Example A-I-1, stepa. The title compound (2.06 g) was obtained after silica gel columnchromatography (0, 1, 2, 3% ethanol in dichloromethane). R_(f) (2%MeOH/CHCl₃) 0.40.

¹H-NMR (CDCl₃): 7.95 (d, 2H, 7.35 (d, 2H), 6.91 (d, 2H), 6.83 (d, 2H),5.27 (s, 2H), 3.81 (s, 3H), 1.72 (s, 1H).

b) 4-Methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate.

4-Methoxybenzyl 4-hydroxybenzoate was acylated withN-benzyloxycarbonyl-L-valine by the method described in Example A-I-1,step b. The title compound (2.71 g) was obtained after silica gel columnchromatography (0, 1% ethanol in dichloromethane). R_(f) (2% MeOH/CHCl₃)0.70.

¹H-NMR (CDCl₃): 8.05 (d, 2H), 7.34 (m, 7H), 7.14 (d, 2H), 6.92 (d, 2H),5.35 (d, 1H), 5.28 (s, 2H), 5.18 (s, 2H), 4.55 (d,d, 1H), 3.81 (s, 3H),2.34 (m, 1H), 1.10 (s, 3H), 0.95 (d, 3H).

c) 4-(N-benzyloxycarbonyl-L-valyloxy) benzoic acid.

4-Methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate wasde-esterified by the method described in Example A-I-1, step c. Thetitle compound (1.86 g) was obtained after silica gel columnchromatography (2, 10, 20% ethanol in dichloromethane). R_(f) (2%MeOH/CHCl₃) 0.20. The compound can be activated and esterifed directlyto a drug or further modifed as described below.

¹H-NMR (CDCl₃): 8.15 (d, 2H), 7.34 (m, 5H), 7.22 (d, 2H), 5.38 (d, 1H),5.17 (s, 2H), 4.58 (d,d, 1H), 2.34 (m, 1H), 1.12 (s, 3H), 0.96 (d, 3H).

d) Chloromethyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate.

4-(N-benzyloxycarbonyl-L-valyloxy) benzoic acid was esterified by themethod described in Example A-I-1, step d. The title compound (0.95 g)was obtained after silica gel column chromatography (0, 1% ethanol indichloromethane). R_(f) (2% MeOH/CHCl₃) 0.80.

¹H-NMR (CDCl₃): 8.12 (d, 2H), 7.36 (m, 5H), 7.20 (d, 2H), 5.94 (s, 2H),5.32 (d, 1H), 5.15 (s, 2H), 4.55 (d,d, 1H), 2.34 (m, 1H), 1.10 (s, 3H),1.03 (d, 3H).

e) Iodomethyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate.

Chloromethyl 4-(N-benzyloxycarbonyl-L-valyloxy) benzoate was convertedto iodide by the method described in Example A-I-1, step e to give thetitle compound (1.16 g) practically pure. R_(f) (2% MeOH/CHCl₃) 0.80.

¹H-NMR (CDCl₃): 8.11 (d, 2H), 7.35 (m, 5H), 7.21 (d, 2H), 6.15 (s, 2H),5.32 (d, 1H), 5.14 (s, 2H), 4.55 (d,d, 1H), 2.34 (m, 1H), 1.10 (s, 3H),1.03 (d, 3H).

EXAMPLE A-1-8 Iodomethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate

a) 4-Methoxybenzyl 2,2-dimethyl-4-pentenoate

To a solution of 2,2-dimethyl4-pentenoic acid (11.5 g, 90 mmol) in DMF(250 mL) at room temperature, was added potassium tert-butoxide (11.1 g,99 mmol). The reaction mixture was stirred at 60° C. for 1 h.4-Methoxybenzyl chloride (16.9 g, 108 mmol) was added and the reactionmixture was stirred at 60° C. for 4 h. The DMF was evaporated undervacuum, the residue was dissolved in ether (500 mL) and washed withwater (3×200 mL). The organic phase was dried with Na₂SO₄ and evaporatedto give 21.4 g of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate.

¹H-NMR (CDCl₃): 7.27 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 5.8-5.6(m, 1H), 5.1-4.9 (m, 2H), 5.03 (s, 2H), 3.80 (s, 3H), 2.27 (d, 2H), 1.17(s, 6H).

b) 4-Methoxybenzyl 5-hydroxy-2,2-dimethylvalerate

A mixture of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate (9.50 g, 38 mmol)and 9-BBN (115 mL, 57 mmol, 0.5 M in THF) was stirred at 60° C. for 60min, whereupon the reaction mixture was cooled to −5° C. H₂O (35 mL) wasadded, the reaction mixture was stirred for 5 min at −5° C., an aqueoussolution of NaOH (35 mL, 3M) was added and the reaction mixture wasstirred for a further 10 min at −5° C. An aqueous solution of H₂O₂ (35mL, 30%) was added dropwise and the temperature of the reaction mixturewas allowed to assume room temperature, whereupon the reaction mixturewas stirred for 30 min at room temperature. After evaporation, water(200 mL) was added and the resulting mixture was extracted with CH₂Cl₂(5×200 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was columnchromatographed (silica gel, 1→8% MeOH in CH₂Cl₂), to give 6.32 g of4-methoxybenzyl 5-hydroxy-2,2-dimethylvalerate.

¹H-NMR (CDCl₃): 7.27 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 5.03 (s,2H), 3.79 (s, 3H), 3.53 (t, 2H), 1.88 (m, 1H), 1.61-1.52 (m, 2),1.49-1.38 (m, 2H), 1.16 (s, 6H).

c) 4-Methoxybenzyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate

To a mixture of DCC (9.41 g, 46 mmol), DMAP (0.586 g, 4.8 mmol) andN-CBz-L-valine (12.1 g, 48 mmol) in CH₂Cl₂ (200 mL) at 0° C., was addeddropwise a solution of 4-methoxybenzyl 5-hydroxy-2,2-dimethyl-valerate(6.40 g, 24 mmol) in CH₂Cl₂ (50 mL). After 1 h at 0° C., the temperatureof the reaction mixture was allowed to assume room temperature and theftthe mixture was stirred for 5 h at room temperature. The mixture wasfiltered through a glass filter and the solvent was removed underreduced pressure. The crude product was column chromatographed (silicagel, 1→4% MeOH in CH₂Cl₂), to give 8.61 g 4-methoxybenzyl5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate.

¹H-NMR (CDCl₃): 7.36 (s, 5H), 7.28 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz,2H), 5.39 (d, 1H), 5.12 (s, 2H), 5.05 (s, 2H), 4.30 (dd, 1H), 4.10-4.02(m, 2H), 3.80 (s, 3H), 2.28-2.07 (m, 1H), 1.62-1.48 (m, 4H), 1.19 (s,6H), 0.97 (d, 3H), 0.89 (d, 3H).

d) 5-(N-CBz-L-valyloxy)-2,2-dimethylvaleric acid

To a solution of 4-methoxybenzyl5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate (8.24 g, 16.5 mmol) in CH₂Cl₂(100 mL) at room temperature, was added trifluoroacetic acid (5 mL).After 1 h at room temperature, the reaction mixture was concentratedunder reduced pressure. The crude product was column chromatographed(silica gel, 3→5% MeOH in CH₂Cl₂), to give 6.00 g of5-(N-CBz-L-valyloxy)-2,2-dimethylvaleric acid. The compound can beactivated and directly esterified to a drug or further modified asdescribed below.

¹H-NMR (CDCl₃): 10.94 (br s, 1H), 7.35 (s, 5H), 5.45 (d, 1H), 5.11 (s,2H), 4.30 (dd, 1H), 4.21-4.00 (m, 2H), 2.28-2.07 (m, 1H), 1.68-1.51 (m,4H), 1.21 (s, 6H), 0.97 (d, 3H), 0.89 (d, 3H).

e) Chloromethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate

To a solution of 5-(N-CBz-L-valyloxy)-2,2-dimethylvaleric acid (5.88 g,15.5 mmol) in dioxane (100 mL), was added dropwise a 40% aqueoussolution of tetrabutylammonium hydroxide (10.1 g). After stirring for 5min, the solution was evaporated to dryness through co-evaporation withdioxane and toluene. The residue was dissolved in dichloromethane (100mL) and then chloroiodomethane (11.3 mL, 155 mmol) was added and thesolution was stirred for 6 h at room temperature. The solution wasconcentrated under reduced pressure and the residue was shaken withhexane/ethyl acetate (1:1 v/v, 200 mL). The yellow crystalline solid wasfiltered off and the filtrate was washed with aqueous solution of sodiumthiosulfate (0.1 M) and the filtered through anhydrous sodium sulfateand evaporated to dryness. The residue was column chromatographed(silica gel, 1-4% MeOH in CH₂Cl₂), to give 3.95 g of chloromethyl5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate.

¹H-NMR (CDCl₃): 7.34 (s, 5H), 5.69 (s, 2H), 5.35 (d, 1H), 5.10 (s, 2H),4.29 (dd, 1H), 4.20-4.00 (m, 2H), 2.24-2.06 (m, 1H), 1.65-1.50 (m, 4H),1.20 (s, 6H), 0.96 (d, 3H), 0.88 (d, 3H).

f) Iodomethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate

To a solution of chloromethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate(3.85 g, 9 mmol) in acetonitrile (50 mL), was added sodium iodide (5.40g, 36 mmol). The solution was stirred for 4 h at 60° C. The resultingsuspension was filtered and the filtrate was evaporated. The residue wasdissolved in CH₂Cl₂ and washed with aqueous sodium thiosulfate (0.1 M).The organic phase was dried (Na₂SO₄) and concentrated under reducedpressure. The crude product was column chromatographed (silica gel, 1%MeOH in CH₂Cl₂), to give 4.26 g of iodomethyl5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate

¹H-NMR (CDCl₃): 7.34 (s, 5H), 5.90 (s, 2H), 5.32 (d, 1H), 5.10 (s, 2H),4.29 (dd, 1H), 4.18-4.02 (m, 2H), 2.26-2.08 (m, 1H), 1.65-1.50 (m, 4H),1.17 (s, 6H), 0.97 (d, 3H), 0.89 (d, 3H).

EXAMPLE A-1-9 2-(N-CBz-L-valyloxy)-ethyl iodomethyl carbonate

a) 2-(N-CBz-L-valyloxy)-ethanol

To a mixture of DCC (11.4 g, 55 mmol), DMAP (0.611 g, 5 mmol) andethyleneglycol (55.8 mL, 1 mol) in CH₂Cl₂ (300 mL) at 0° C., was addeddropwise a solution of N-CBz-L-valine (12.6 g, 50 mmol) in CH₂Cl₂ (100mL). After 1 h at 0° C., the temperature of the reaction mixture wasallowed to assume room temperature and then the mixture was stirred for5 h at room temperature. The mixture was filtered through a glass filterand the solvent was removed under reduced pressure. The crude productwas column chromatographed (silica gel, 5→10% MeOH in CH₂Cl₂), to give12.0 g 2-(N-CBz-L-valyloxy)-ethanol.

¹H-NMR (CDCl₃): 7.30 (s, 5H), 5.77 (d, 1H), 5.06 (s, 2H), 4.29-4.12 (m,3H), 3.80-3.66 (m, 2H), 3.46 (m, 1H), 2.22-2.04 (m, 1H), 0.94 (d, 3H),0.88 (d, 3H).

b) 2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate

To a mixture of 2-(N-CBz-L-valyloxy)-ethanol (12. 0 g, 40.6 mmol) andpyridine (19.7 mL, 0.24 mmol) in CH₂Cl₂ (300 mL) at 0° C., was addeddropwise chloromethyl chloroformate (10.5 g, 81.2 mmol). After 30 min at0° C., the reaction mixture was washed with H₂O (200 mL). The H₂O phasewas washed with CH₂Cl₂ (100 mL) and the solvent of the combined organicphases was removed under reduced pressure. The crude product was columnchromatographed (silica gel, 0.5→1% MeOH in CH₂Cl₂), to give 8.26 g2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate.

¹H-NMR (CDCl₃): 7.35 (s, 5H), 5.71 (s, 1H), 5.28 (d, 1H), 5.11 (s, 2H),4.48-4.26 (m, 5H) 2.28-2.10 (m, 1H), 0.97 (d, 3H), 0.89 (d, 3H).

c) 2-(N-CBz-L-valyloxy)-ethyl iodomethyl carbonate

To a solution of 2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate (3.88g, 10 mmol) in acetonitrile (50 mL), was added sodium iodide (7.50 g, 50mmol). The solution was stirred for 4 h at 60° C. The resultingsuspension was filtered and the filtrate was evaporated. The residue wasdissolved in CH₁Cl₂ and washed with aqueous sodium thiosulfate (0.1 M).The organic phase was dried (Na₂SO₄) and concentrated under reducedpressure, to give 4.51 g 2-(N-CBz-L-valyloxy)-ethyl iodomethylcarbonate.

¹H-NMR (CDCl₃): 7.34(s, 5H), 5.93 (s, 2H), 5.26 (d, 1H), 5.11 (s, 2H),4.48-4.26 (m, 5H) 2.28-2.10 (m, 1H), 0.97 (d, 3H), 0.90 (d, 3H).

EXAMPLE A-I-10 2.2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acidiodomethyl ester

a) 2,2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acid

To a solution of 2,2-dimethyl propionic acid 4-methoxybenzyl ester (4.7g, 20 mmole) and N-CBz-D-valine (5.5 g, 22 mmole) in dichloromethane(100 ml) were added 4-dimethyaminopyridine (305 mg, 2.5 mmole) and DCC(5.15 g, 25 mmole). After 18 hr. the solution was washed successivelywith sodium bicarbonate aqueous solution, citric acid solution andwater. The organic phase was dried and the residue was dissolved indichloromethane (100 ml). To the solution was added trifluoroacetic acid(10 ml). After 3 hr, it was evaporated and the product was isolated withsilica gel column chromatography. 4.5 g. The compound may be activatedand esterfied to a drug or further modified as described below.

¹H-NMR (CDCl₃): 7.36 (m, 5H) 5.11 (s, 2H) 4.30 (m, 1H) 4.18 (dd, 2H)2.17 (m, 1H), 1.23 (d, 6H) 0.93 (m, 6H)

b) 2,2-dimethyl-3-(N-CBz-D-Valyloxy )-propionic acid chloromethyl ester

(2,2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acid (4.5 g, 12.8 mmole)was dissolved in dioxane (20 ml). To the solution was addedtetrabutylammonium hydroxide aqueous solution (40%, 8.3 ml, 12.8 mmole).The solution was dried in vacuo, and it was coevaporated with tolueneseveral times. The residue was dissolved in methylene chloride and thenchloroiodomethane (18 ml, 260 mmole) was added to the solution. After 18hr, the reaction solution was evaporated and the product was isolatedwith silica gel column chromatography. 3.5 g.

¹H-NMR (CDCl₃): 7.34 (m, 5 H) 5.72 (s, 2H) 5.23 (d, 1H) 5.11 (s, 2H)4.31 (m, 1H) 4.14 (dd, 2H) 2.15 (m, 1H) 1.25 (d, 6H), 0.92 (m, 6H).

c) 2,2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acid iodomethyl ester

2,2-Dimethyl-3-(N-CBz-D-valyloxy)-propionic acid chloromethyl ester (2.4g, 6 mmole) was dissolved in acetonitrile (30 ml). Sodium iodide (1.26g, 8.4 mmole) was added to the solution. After reaction at 70° C. for 2hr, the reaction mixture was filtered and the residue was dissolved inmethylene chloride (20 ml) and refiltered. The solution was dried andgave the titled product. 2.68 g.

¹H-NMR (CDCl₃): 7.36 (m, 5H) 5.90 (dd, 2H) 5.26 (d, 1H) 5.11 (s, 2H)4.31 (m, 1H) 4.15 (dd, 2H) 2.18 (m, 1H) 1.22 (d, 6H) 0.92 (m, 6H).

EXAMPLE A-1-11 4-(N-CB2-L-valyloxy) butyric acid iodomethyl ester

a) 4-(N-CBz-L-valyloxy) butyric acid t-butyl ester

N-CBz-L-valine (16.25 g, 65 mmole) was dissolved in DMF (40 ml). To thesolution was added potassium t-butoxide (7.24 g, 65 mmole). After 10min, 4-bromobutyric acid t-butyl ester (12 g, 53 mmole) was added. Thereaction mixture was kept at 65° C. for 2.5 hr and then poured intosodium bicarbonate aqueous solution and extracted with dichloromethane.The organic phase was dried and the product was isolated with silica gelcolumn chromatography. 20.1 g.

¹H-NMR (CDCl₃): 7.38 (m, 5H) 5.32 (d, 1H) 5.13 (s, 2H) 4.32 (dd, 1H)4.28 (t, 2H) 2.31 (t, 2H) 2.18 (m, 1H) 1.97 (m, 2H) 1.45 (s, 9H) 0.97(m, 6H).

b) 4-(N-CBz-L-valyloxy)butyric acid chloromethyl ester

4-(N-CBz-L-valyloxy) butyric acid t-butyl ester (20 g, 50.8 mmole) wastreated with trifluoroacetic acid (30 ml) at 0° C. for 3 h and thenevaporated. The residue was coevaporated with toluene several time. Theintermediate acid (2.56 g, 7.6 mmole) was dissolved in dioxane (10 ml)and to the solution was added tetrabutylammonium hydroxide (40%, 4.66ml, 7.2 mmole). The solution was dried and dissolved in dichloromethane(20 ml) and then chloroiodomethane (10 ml, 144 mmole) was added to thesolution. After 18 hr, the reaction solution was evaporated and theproduct was isolated with silica gel column chromatography. Yield 2.1 g.

¹H-NMR (CDCl₃): 7.34 (m, 5H) 5.69 (dd, 2 H) 5.29 (d, 1H) 5.11 (s, 2H)4.29 (dd, 1H) 4.18 (t, 2H) 2.49 (t, 2H) 2.14 (m, 1H) 2.04 (m, 2H) 0.93(dd, 6H). c) 4-(N-CBz-L-valyloxy)butyric acid iodomethyl ester

4-(N-CBz-L-valyloxy) butyric acid chloromethyl ester (1.54 g, 4 mmole)was dissolved in acetonitrile (15 ml). Sodium iodide (840 mg, 5.6 mmole)was added to the solution. After reaction at 55° C. for 3 hr, thereaction mixture was filtered and the residue was dissolved in methylenechloride (20 ml) and refiltered. The solution was dried and gave thetitled product. Yield 1.9 g.

¹H-NMR (CDCl₃): 7.36 (m, 5H) 5.90 (dd, 2 H) 5.25 (d, 1H) 5.11 (s, 2H)4.29 (dd, 1H 4.18 (t, 2H) 2.43 (t, 2H) 2.20 (m, 1H) 2.00 (m, 2H) 0.93(dd, 6H).

EXAMPLE A-I-12 Iodomethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate

a) 4-Methoxybenzyl 3-hydroxybenzoate

To a solution of 3-hydroxybenzoic acid (6.9 g, 50 mmole) in DMF (100 ml)was added potassium-tert.-butoxide (6.17 g, 55 mmole) and the mixturewas stirred at room temperature for one hour. 4-Methoxybenzyl chloride(9.4 g, 60 mmole) was added and the mixture was stirred for 16 hours at60° C. The mixture was evaporated under reduced pressure and ethylacetate (250 ml) were added. The organic phase was washed five timeswith water, dried with sodium sulfate and evaporated under reducedpressure. The product was isolated by silica gel column chromatographywith toluene/acetone. Yield: 10.5 g=81%

¹H-NMR (CDCl₃) 3.82 (s, 3H) 5.29 (s, 2H) 6.90-7.61 (m, 8H)

b) 4-Methoxybenzyl 3-(N-benzyloxycarbonyl-L-valyloxy) benzoate.

To a cooled solution of 4-methoxybenzyl 3-hydroxybenzoate (7.7 g, 29.8mmole), 4-dimethytaminopyridine (0.73 g, 6 mmole) andN-benzyloxycarbonyl-L-valine (8.3 g, 33 mmole) in 100 ml dichloromethanewas added dicyclohexyl-carbodiimide (7.22 g, 35 mmole) and the mixturewas stirred for 2 days at room temperature. The mixture was cooled andthe urethane was filtered. The solution was evaporated and ethyl acetate(250 ml) was added. The organic phase was washed twice with 5% aceticacid; 5% sodium hydrogencarbonate and water. The organic phase was driedwith sodium sulfate and evaporated under reduced pressure. The productwas isolated by silica gel column chromatography with hexane/ethylacetate. Yield: 13.9 g=94%

¹H-NMR (DMSO d-6) 0.98(m, 6H) 2.20 (m, 1H) 3.72 (s, 3H) 4.14 (m, 1H)5.06 (s, 2H) 5.30 (s, 2H) 6.98-7.86 (m, 14 H)

c) 3-(N-benzyloxycarbonyl-L-valyloxy) benzoic acid

To a solution of4-methoxybenzyl-3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate (13.7 g,27.8 mmole) in dichloromethane (150 ml) was added trifluoroacetic acid(20 ml) and the mixture was stirred for 2 hours at room temperature. Thesolution was evaporated under reduced pressure and the productcrystallized from toluene. Yield: 10.1 g=87%. The compound can beactivated and esterified to a drug or further modified as describedbelow

¹H-NMR (DMSO d-6) 1.01 (m, 6H) 2.21 (m, 1H) 4.17 (d, d, 1H) 5.08 (s, 2H)7.28-7.96 (m, 10H)

d) Chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate.

To a solution of 3-(N-benzyloxycarbonyl-valyloxy)benzoic acid (7.42 g,20 mmole) in 1,4-dioxane (100 ml) was added a 40% solution oftetrabutylammonium hydroxide (12.97 g, 20 mmole) and the mixture wasstirred 2 hours at room temperature. The mixture was evaporated underreduced pressure and co-evaporated two times with 1,4-dioxane and twotimes with toluene. The dried product was dissolved in dichloromethane(50 ml) and chloroiodomethane (35.3 g, 200 mmole) was added. Thesolution was stirred for two days at room temperature and evaporatedunder reduced pressure. Ethyl acetate (100 ml) was added and the organicphase washed twice with water, dried with sodium sulfate and evaporatedunder reduced pressure: The product was isolated by silica gel columnchromatography. Yield: 3.8 g=45%.

¹H-NMR (CDCl₃) 1.02 (m, 6H) 2.36 (m, 1H) 4.53 (d, d, 1H) 5.14 (s, 2H)5.30 (d, 1H) 7.26 (m, 6H) 7.39 (t, 1H) 7.79 (s, 1H) 7.96 (d, 1H)

e) Iodomethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate

To a solution of chloromethyl3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate (2.0 g, 4.76 mmole) in dryacetone (30 ml) was added sodium iodide (3.15 g, 21 mmole) and themixture was stirred overnight at room temperature. The mixture wasevaporated under reduced pressure and extracted with ethyl actate/water.The organic phase was washed with a 5% sodium thiosulfate solution,dried with sodium sulfate and evaporated under reduced pressure. Yield:2.3 g=94%.

¹H-NMR (CDCl₃) 1.02 (m, 6H) 2.38 (m, 1H) 4.56 (d, d, 1H) 5.14 (s, 2H)5.30 (d, 1H) 6.14 (s, 2H) 7.26-7.50 (m, 7H) 7.80(s, 1H) 7.96 (d, 1H)

EXAMPLE A-I-13 Iodomethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-propionate

a) 3-buten-1-yl-3-(N-benzyloxycarbonyl)-propionate.

To a solution of 3-buten-1-ol (2.16 g, 30 mmole),N-benzyloxycarbonyl-1-valine (8.29 g, 33 mmole) and4-dimethylaminopyridine (0.37 g, 3 mmole) in dichloromethane (80 ml) wasadded dicyclohexyl-carbodiimide (7.22 g, 35 mmole) and the mixture wasstirred overnight at room temperature. The mixture was cooled and theurethane was filtered. The solution was evaporated under reducedpressure and ethyl acetate (200 ml) was added. The organic phase waswashed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water.The organic phase was dried with sodium sulfate and evaporated underreduced pressure. The product was isolated by silica gel columnchromatography with hexane/ethyl acetate. Yield: 8.3 g=90%.

¹H-NMR (CDCl₃) 0.92 (m, 6H) 2.18 (m, 1H) 2.40 (m, 2H) 4.20 (m, 3H) 5.10(m, 4H) 5.26 (d, 1H) 5.75 (m, 1H) 7.30 (m, 5H)

b) 3-(N-benzyloxycarbonyl-L-valyloxy)-propanoic acid

To a solution of 3-buten-1-yl-3-(N-benzyloxycarbonyl-L-valyloxy)-propionate (9.2 g, 30 mmole) in 150ml benzene was added tetrabutylammonium bromide (1.62 g, 5 mmole) and100 ml water. The mixture was cooled to about 5° C. and potassiumpermanganate (14.82 g, 90 mmole) was added in portions. The mixture wasstirred 2 hours at room temperature, diluted with water and decolorizedby the addition of sodium bisulfite. The mixture was acidified with 2Mhydrogen chloride and extracted 3 times with ethyl acetate. The combinedorganic phases were washed with water and dried with sodium sulfate. Thesolution was evaporated under reduced pressure and the product isolatedby silica gel column chromatography with hexane/ethyl acetate. Yield:5.4 g=55%. The compound can be activated and esterified to a drug orfurther modified as described below.

¹H-NMR (DMSO d-6) 0.90 (m, 6H) 2.5 (m, 2H) 3.88 (d, d, 1H) 4.32 (m, 2H)5.03 (s, 2H) 7.36 (m, 5H) 7.68 (d, 1H)

c) Chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-propionate.

To a solution of 3-(N-benzyloxycarbonyl-L-valyloxy)propanoic acid (5.2g, 16.08 mmole) in 1,4-dioxane (50 ml) was added a 40% solution oftetrabutylammonium hydroxide (10.43 g, 16.08 mmole) and the mixture wasstirred 2 hours at room temperature. The mixture was evaporated underreduced pressure and co-evaporated two times with 1,4-dioxane and twotimes with toluene. The dried product was dissolved in 40 mldichloromethane and chloroiodomethane (28.4 g. 160 mmole) was added. Thesolution was stirred for two days at room temperature and evaporatedunder reduced pressure. Ethyl acetate (100 ml) was added and the organicphase washed twice with water, dried with sodium sulfate and evaporatedunder reduced pressure. The product was isolated by silica gel columnchromatography. Yield: 2.2 g=35%

¹H-NMR (CDCl₃) 0.90 (m, 6H) 2.14 (m, 1H) 2.75 (m, 2H) 4.38 (m, 3H) 5.11(s, 2H) 5.71 (s, 2H) 7.36 (m, 5H)

d) Iodomethyl3-(N-benzyloxycarbonyl-L-valyloxy)-propionate

To a solution of chloromethyl3-(N-benzyloxycarbonyl-L-valyloxy)-propionate (2.05 g, 5.51 mmole) indry acetone (50 ml) was added sodium iodide (4.12 g, 27.5 mmole) and themixture was stirred overnight at room temperature. The mixture wasevaporated under reduced pressure and extracted with ethyl acetatewater. The organic phase was washed with a 5% sodium thiosulfatesolutions dried with sodium sulfate and evaporated under reducedpressure. Yield: 2.35 g=92%.

¹H-NMR (CDCl₃) 0.94 (m, 6H) 2.17 (m, 1H) 2.68 (t, 2H) 4.40 (m, 3H) 5.12(s, 2H) 5.91 (s, 2H) 7.26 (m, 5H).

EXAMPLE C-I-1 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl1-iodoethyl carbonate

(a) 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1-chloroethylCarbonate

To a solution of 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propanol(0.545 g, 1.11 mmol) in 5 mL dry CH₂Cl₂ were added pyridine (540 μL,6.68 mmol), with cooling and stirring in an ice bath, followed by1-chloroethyl chloroformate (242 μL, 2.22 mmol). After 1 h, the reactionmixture was diluted with 5 mL CH₂Cl₂ and washed with water (5 mL) andbrine (5 mL). The organic phase was dried over anhydrous Na₂SO₄ andconcentrated on a rotavapor, coevapoating several times with toluene.Column chromatogaphy (silica, 4/1 petroleum ether-ethyl acetate) gavethe chloride (596 mg, 90%) as a white solid.

¹H NMR (250 Mz, CDCl₃) δ 0.77 and 0.83 (2d, 6H each, J=6.8 Hz), 1.31 (s,18H), 1.70 (d, 3H, J=5.8 Hz), 2.00 (m, 2H), 4.08-4.41 (m, 6H), 5.01-5.09(m, 3H), 6.30 (q, 1H, J=5.7 Hz).

(b) 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1-iodoethylCarbonate

A mixture of the chloride (596 mg, 1.0 mmol) from step (a) and NaI (684mg, 4.57 mmol) in 10 ml dry MeCN was refluxed at 80° C. for 4 h. Thereaction mixture was concentrated under vacuum and then partitionedbetween 30 mL diethyl ether and 10 mL water. The organic phase waswashed with 5% aqueous sodium thiosulfate (2×5 mL), and the last aqueouslayer was reextracted with ether (5 mL). The organic phases werecombined, washed with brine, dried over Na₂SO₄, and concentrated.

Flash column chromatography (silica, 4/1 petroleum ether-ethyl acetate)gave a fraction (275 mg) containing 80% iodide, as determined from ¹HNMR, and small amounts of the starting chloride and alkene from theelimination side reaction.

¹H NMR (250 MHz, CDCl₃) δ 0.81-0.85 (m, 6H), 0.88-0.92 (m, 6H), 1.37 (s,18H), 2.05 (m, 2H), 2.17 (d, 3H, J=6.1 Hz), 4.12-4.46 (m, 6H), 5.00 (d,2H, J=8.8 Hz), 5.11 (m, 1H), 6.68 and 6.69 (2 sets of q, 1H, J=6.1 Hz).

EXAMPLE A-I-14 3-(N-benzyloxycarbonyl-L-valyloxy)-2,2-dimethylpropyliodomethyl carbonate

(a) 3-(N-benzyloxycarbonyl-L-valyloxy )-2,2-dimethyl-1-propanol

A mixture of N-benzyloxycarbonyl-L-valine (2.50 g, 10.0 mmol),2,2-dimethyl-1,3-propanediol (5.30 g, 50.9 mmol),dicyclohexylcarbodiimide (2.60 g, 12.6 mmol), and4-dimethylaminopyridine (125 mg, 1.0 mmol) in 100 mL dry CH₂Cl₂ wasstirred for 23 h. The reaction mixture was filtered and washedsuccessively with 50 mL each of water, saturated aqueous NH₄Cl,saturated aqueous NaHCO₃, and water. The organic phase was dried overanhydrous Na₂SO₄ and concentrated. The title compound (2.99 g, 87%) wasisolated by flash column chromatography (silica, 2/1 petroleumether-ethyl acetate) as a white waxy solid.

¹H NMR (250 MHz, CDCl₃) δ 0.89 and 0.97 (2d, 3H each, J=6.8 Hz), 0.90(s, 6H), 2.16 (m, 1H), 2.49 (br s, 1H), 3.25-3.3 7 (m, 2H), 3.96 (s,2H), 4.28 (dd, 1H, J=8.9, 4.8 Hz), 5.09 (s, 2H), 5.41 (d, 1H, J=8.7 Hz),7.34 (s, 5H).

(b) 3(N-benzyloxycarbonyl-L-valyloxy)-2,2-dimethylpropyl chloromethylcarbonate

Chloromethyl chloroformate (1.50 mL, 16.6 mmol) was added to a solutionof the alcohol (2.74 g, 8.12 mmol) from step (a) and pyridine (4.9 mL,61 mmol) in 40 mL dry CH₂Cl₂, in an ice bath. After stirring for 1 h,the mixture was diluted with CH₂Cl₂ and washed successively with water,saturated NaHCO₃, and brine. The organic phase was dried over anhydrousNa₂SO₄ and concentrated, coevaporating several times with toluene on arotavapor. Flash column chromatography (silica, 2/1 petroleumether-ethyl acetate) gave 3.31 g (95%) of the title compound.

¹H NMR (250 MHz, CDCl₃) δ 0.88 and 0.96 (2d, 3H each, J=6.9 Hz), 0.98(s, 6H), 2.16 (m, 1H), 3.94 and 4.02 (2s, 2H each), 4.31 (dd, 1H, J=9.0,4.7 Hz), 5.10 (s, 2H), 5.33 (d, 1H, J=9.0 Hz), 5.68 and 5.70 (ABq, 2H,J_(AB)=6.3 Hz), 7.34 (s, 5H).

(c) 3-(N-benzyloxycarbonyl-L-valyloxy)-2,2-dimethylpropyl iodomethylcarbonate

A mixture of the chloride (3.14 g, 7.30 mmol) from step (b) and NaI(4.37 g, 29.2 mmol) in 73 mL dry MeCN was refluxed at 80° C. for 3 h.After removal of solvent under vacuum, the mixture was partitionedbetween 80 mL ethyl acetate and 40 mL water. The organic phase waswashed with 5% Na₂S₂O₃, and then brine, dried over anhydrous Na₂SO₄, andconcentrated. Flash column chromatography (silica, petroleum ether-ethylacetate) gave 3.68 g (97%) of the title compound.

¹H NMR (250 MHz, CDCl₃) δ 0.88 and 0.96 (2d, 3H each), 0.98 (s, 6H),2.18 (m, 1H), 3.94 and 4.02 (2s, 2H each), 4.32 (dd, 1H, J=9.0, 4.7 Hz),5.11 (s, 2H), 5.26 (d, 1H), 5.92 and 5.93 (ABq, 2H, J_(AB)=5.1Hz), 7.35(s, 5H).

EXAMPLE A-I-15 1-(N-benzyloxycarbonyl-L-valyloxy)-2-methyl-2-propyliodomethyl carbonate

(a) 1-(N-benzyloxycarbonyl-L-valyloxy)-2-methyl-2-propanol

N-Benzyloxycarbonyl-L-valine (2.02 g, 8.0 mmol), 4-dimethylaminopyridine(100 mg, 0.8 mmol), and), and dicyclohexylcarbodiimide (2.04 g, 9.9mmol, is 20 mL CH₂Cl₂) were added to 2-methyl-1,2-propanediol (12.2mmol) in 30 mL dry CH₂Cl₂, with cooling in an ice bath. DMF (5 mL) wasadded. After stirring for 5 h at 10° C., the reaction mixture wasfiltered, concentrated, and then redissolved in ethyl acetate. Theorganic solution was washed with saturated NaCl, dried over anhydrousNa₂SO₄, and concentrated. Flash column chromatography (silica, 2/1petroleum ether-ethyl acetate) gave 2.3 g of the title compound.

¹H NMR (250 MHz, CDCl₃) δ 0.91 (d, 3H), 0.98 (d, 3H), 1.23 (s, 6H), 2.17m, 1H), 4.02 (s, 2H), 4.31 (m, 1H), 5.10 (s, 2H): 5.26 (m, 1H), 7.35 (s,5H).

(b) 1-(N-benzyloxycarbonyl-L-valyloxy)-2-methyl-2-propyl Chloromethylcarbonate

All of the alcohol from above was dissolved in 35 mL dry CH₂Cl₂ andcooled in an ice bath. Pyridine (3.50 mL, 43.4 mmol) was added, followedby chloromethyl chloroformate (1.30 mL, 14.4 mmol). After 1 h, the icebath was removed and stirring was continued for 2 h at ambienttemperature. The mixture was diluted with CH₂Cl₂ (50 mL) and washed withwater (50 mL), and then brine (2×25 mL). Drying over anhydrous Na₂SO₄ ofthe combined organic phases and concentration under vacuum,coevaporating several times with toluene, gave a yellow-brown oil thatwas subjected to flash column chromatography (silica, 2/1 petroleumether-ethyl acetate) to yield 2.86 g (86% fromN-benzyloxycarbonyl-L-valine) of the title compound.

¹H NMR (250 MHz, CDCl₃) δ 0.90 and 0.98 (2d, 3H each, J=6.9 Hz), 1.53(s, 6H), 2.19 (m, 1H), 4.23 and 4.41 (ABq, 2H, J_(AB)=11.8 Hz), 4.36(dd, 1H, J=9.1, 4.6 Hz), 5.11 (s, 2H), 5.26 (d, 1H, J=9.1 Hz), 5.65 and5.67 (ABq, 2H, J_(AB)=6.3 Hz), 7.36 (br s, 5H).

(c) 1-(N-benzyloxycarbonyl-L-valyloxy)-2-methyl-2-propyl Iodomethylcarbonate

A mixture of the chloride (2.84 g, 6.84 mmol) from step (b) and NaI(4.15 g, 27.2 mmol) in 68 mL dry acetonitrile was refluxed at 75° C. for4 h. After evaporation of solvent under vacuum, the residue waspartitioned between ethyl acetate (80 mL) and water (40 mL), and theorganic layer was washed with 5% Na₂S₂O₃ (15 mL) and brine (25 mL).Drying the organic phase over anhydrous Na₂SO₄ and concentration gave ayellow oil that was subjected to flash column chromatography (silica,2/1 petroleum ether-ethyl acetate) to furnish 3.29 g (95%) of the titlecompound.

¹H NMR (250 MHz, CDCl₃) δ 0.90 and 0.94 (2d, 3H each, J=6.8 Hz), 1.52(s, 6H), 2.17 (m, 1H), 4.35 (m, 1H), 4.22 and 4.39 (ABq, 2H, J_(AB)=11.7Hz), 5.10 (s, 2H), 5.30 (d, 1H), 5.86 (s, 2H), 7.34 (s, 5H)

EXAMPLE A-I-16 Iodomethyl 3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate

a) 4-Methoxybenzyl-3,4-dihydroxyhydrocinnamate

3,4-Dihydroxycinnamic acid (6.5 g, 35.7 mmol) was dissolved in DMF (50ml) and cooled to 0° C. on an ice-bath. 4-Potassium tert-butoxide (35.7mmol), was then added and the mixture was left for approximately 30 minat 0° C., followed by dropwise adition of 4-methoxy-benzylchloride (39mmol) in DMF (25 ml). The mixture was allowed to reach room temperatureand left over-night. The solvent was then evaporated and the crudeproduct was purified by chromatography (ethyl acetate-hexane, 1:1) togive 6 g of the title compound (55%).

¹H NMR (CDCl₃ 45° C.): 7.24-6.57 (m, 7H), 5.03 (s, 2H), 3.80 (s, 3H),2.83 (t, 2H), 2.58 (t, 3f).

b) 4-Methoxybenzyl-3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate

4-Methoxybenzyl-3,4dihydroxyhydrocinnamate (5 g, 16.5 mmol),N,N-dimethylaminopyridine (2 g, 16.5 mmol), N,N′-dicyclohexylcarbodiimide (8.5 g, 41.3 mmol) and Cbz-L-valine (10.4 g, 41.3 mmol)were dissolved in dichloromethane (50 ml). After 4 h, the the mixturewas filtered and evaporated onto silica gel and purified bychromatography hexane-EtOAc, 5:2→3:2) to give pure title product (10.1g, 79%).

¹H NMR (CDCl₃ 45° C.): 7.24-6.49 (m, 17H), 5.6 (br s, 2H), 5.0 (m, 6H) ,4.45 (m, 1H)), 3.79 (s, 3H), 2.94 (t, 2H), 2.65 (t, 2H), 2.4-2.25 (br m,2H), 1.03 (m, 12H)

c) 3,4-Di-(N-CBZ-L-valyloxy)hydrocinnamic acid

4-Methoxybenzyl-3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate (10 g, 13 mmol)was dissolved in dichloromethane and 1,1,1 trifluoroacetic acid (30 ml)and left at ambient temperature for 3.5 h. Evaporation under reducedpressure and purification by chromatography (chloroform-methanol, 10:1)yielded 6.7 g (80%) pure title product. The compound can be activatedand esterified to a drug or further modified as described below.

¹H NMR (CDCl₃ 45° C.): 7.24-7.0 (m, 13H), 5.65 (br s, 1H), 5.55 (br s,1H), 5.1 (m, 4H), 4.46 (m, 2H), 2.95 (t, 2H), 2.66 (t, 2H), 2.35 (m,2H).

d) Chloromethyl 3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate

3,4-Di-(N-CBZ-L-valyloxy)hydrocinnamic acid (4.2 g, 6.47 mmol) wasdissolved in dioxane (70 ml). Tetrabutylammonium hydroxide was addeddropwise until pH=8. The solvent was then removed under reduced pressureThe solid was redissolved in dioxane (30 ml) and toluene (30 ml) andevaporated. The procedure was repeated twice (for removal of water).Dichloromethane (60 ml) and chloro-iodomethane was added in one portionand the mixture was left at ambient temperature for 6 h. Evaporation ofthe solvent and purification by chromatography yielded 1.7 g titleproduct (38%).

¹H NMR (CDCl₃ 45° C.): 7.3-7.0 (m, 13H), 5.67 (s, 2H), 5.62 (br s, 2H),5.14-5.0 (m, 4H), 4.46 (m, 2H), 2.95 (t, 2H), 2.67 (m, 2H), 1.07-0.99(m, 12H)

e) Iodomethyl 3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate

Chloromethyl 3,4-di-(N-CBZ-L-valyloxy)hydrocinnamate (1.9 g, 2.7 mmol)and sodium iodide (2 g, 13.3 mmol) were dissolved in acetonitrile (50ml) and heated to 65° C. for 60 min. The solvent was removed underreduced pressure and the residue was taken up in dichloromethane andfiltrated. Removal of the solvent and purification by chromatography(ethyl acetate-hexane, 2:5) gave pure title product (1.9 g, 90%)

¹H NMR (CDCl₃ 45° C.): 7.34-7.02 (m, 13H), 5.89 (s, 2H), 5.64 (br s,2H), 5.14-5.02 (m, 4H), 4.47 (m, 2H), 2.96 (t, 2H), 2.64 (t, 2H), 2.33(m, 2H), 1.08-0.99 (m, 12H)

EXAMPLE A-I-17 3-(N-CBZ-L-valyloxy)phenyl iodomethyl carbonate

a) 3-(N-CBz-L-valyloxy)phenol

CBz-L-valine (10 g, 40 mmol), 1,3-dihydroxybenzene (8.7 g, 79 mmol)N,N′dicychlohexylcarbodiimide (10.2 g, 44 mmol) and4-dimethylaminopyridine (2.4 g, 20 mmol) were dissolved in DMF (50 ml)and left at ambient temperature overnight. The reaction mixture wasfiltered, the solvent removed under reduced pressure and the crudeproduct was taken up in dichloromethane and filtered. Removal of thesolvent followed by purification by chromatography (chloroform—methanol,10:1) yielded pure title product (10.9 g, 79%).

¹H NMR (CDCl₃ 45° C.): 7.36-7.32 (m, 6H, 7.20 (t, 1H), 6.71-6.55 (m,2H), 5.2 (br s, 1H), 5.14 (s, 2H), 4.5 (brs, 1H), 2.4-2.3 (m, 1H),1.09-1.01 (m, 6H)

b) (N-CBZ-L-valyloxy)phenyl chloromethyl carbonate

3-(N-CBz-L-valyloxy)phenol (5.4 g, 15 7 mmol) was dissolved indichloromethane (70 ml) and cooled in an ice-bath. Pyridine (1.2 g, 23.5mmol was added followed by dropwise addition of1-chloro-methylchloroformate (2.3 g, 18.8 mmol) in dichloromethane (10ml). The mixture was left at room temperature for 4 h. Water (25 ml) wasthen added and the phases were separated. The organic layer was washedwith 0.0 1 M aqueous hydrochloric acid (25 ml). Purfication bychromatography (ethyl acetate-hexane, 1:1) gave the title compound (4.5g, 65%)

¹H NMR (CDCl₃ 45° C.): 7.38-7.02 (m, 9H), 5.81 (s, 2H), 5.2 (br s, 1H),5.14 (s, 2H), 4.48 (m, 1H), 2.30 (m, 1H), 1.09-1.01 (m, 6H)

c) 3-(N-CBZ-L-valyloxy)phenyl iodomethyl carbonate

(N-CBZ-L-valyloxy)phenyl chloromethyl carbonate (1.5 g, 3.44 mmol) andsodium iodide (2 g, 13.3 mmol) were stirred at 60° C. in acetonitrile(50 ml) for 4.5 h. The mixture was filered the solvent removed and thecrude product was taken up in 100 ml hexane-ethyl acetate, 1:1, andfiltered through a sintered glass funnel, packed with 2 cm silica gel.Removal of the solvent yielded pure title product (1.68 g, 92%)

¹H NMR (CDCl₃ 45° C.): 7.38-7.02 (m, 9H), 6.03 (s, 2H), 5.2 (br s, 1H),5.14 (s, 2H), 4.48 (m, 1H), 2.30 (m,1H), 1.09-1.01 (m,6H)

EXAMPLE A-I-18 Iodomethyl2-(N-CBZ-L-valyloxy)phenylacetate

a) 4-Methoxybenzyl 2-hydroxyphenylacetate.

2-hydroxyphenylacetic acid (10 g, 66 mmol) was dissolved inN,N-dimethyl-formamide (100 ml) and cooled on ice-bath. Potassiumtert-butoxide (8.85 g, 78 mmol) was added. The mixture was left for 30min and allowed to reach room temperature. 4-Methoxy-benzylchloride(11.7 g, 72 mmol) in N,N-dimethyl-formamide (30 ml) was then addeddropwise, under nitrogen atmosphere and left over-night. The solvent wasevaporated under reduced pressure and the crude mixture was dissolved inether (100 ml) and washed with water (25 ml), brine and dried oversodium sulphate. Chromatography (hexane-ethyl acetate, 2:1) followed byrecrystallization (hexane-ethyl acetate) gave the title compound (7.6 g,42%).

¹H NMR (CDCl₃ 45° C.): 7.3-6.8 (m, 8H), 5.01 (s, 2H), 3.81 (s, 3H), 3.67(s, 2H).

b)4-Methoxybenzyl 2-(N-CBz-L-valyloxy)phenylacetate

4-Methoxybenzyl 2-hydroxyphenylacetate 3 g, 11 mmol),N,N-dicyclohexyl-carbodiimide (2.7 g, 13.2 mmol), dimethylaminopyridine(0.134 g, 1.1 mmol) and CBz-L-valine (3.3 g, 13.2 mmol) were dissolvedin dichloromethane (50 ml). After the weekend the solid was filteredoff, the solvent removed under reduced pressure and the crude productpurified by chromatography (ethyl acetate, hexane, 1:2) to give thetitle compound (5.2 g, 93%).

¹H NMR (CDCl₃ 45° C.): 7.36-6.80 (m,13H), 5.4 (br s, 1H), 5.12 (s, 2H),5.03 (s, 2H) 4.50 (m, 1H), 3.79 (s, 3H), 3.56 (s, 2H), 2.30 (m, 1H),1.04 (d, 3H), 0.97 (d, 3H)

c) 2-(N-CBz-L-valyloxy)phenylacetic acid

4-Methoxybenzyl 2-(N-CBz-L-valyloxy)phenylacetate (4.25 g, 8.4 mmol),was dissolved in dichloromethane (40 ml). Triflouroacetic acid (8 ml)was added with cooling on ice. The mixture was allowed to reach roomtemperature and stirred for 40 min. The solvent was removed underreduced pressure and the crude product was recrystallized twice(hexan-ethyl acetate+a small amount of dichloromethane) to give thetitle compound (2.6 g, 80%). The compound can be activated andesterified to a drug or further modified as described below.

¹H NMR (CDCl₃ 45° C.): 7.35-7.08 (m, 9H), 5.35 (br s, 1H), 5.13 (s, 2H),4.48 (m, 1H), 3.57 (s, 2H), 2.33 (m, 1H), 1.08 (d, 3H), 1.02 (d, 3H).

d) Chloromethyl 2-(N-CBZ-L-valyloxy)phenylacetate

This compound was prepared in poor yield from2-(N-CBz-L-valyloxy)phenylacetic acid (5.5 g, 14.3 mmol) by anunoptimized procedure essentially as described in Example A-I-16 d).Yield: 0.265 g

¹H NMR (CDCl₃ 45° C.): 7.28-7.01 (m, 9H), 5.55 (s, 2H), 5.2 (br s, 1H),5.07 (s, 2H), 4.43 (m, 1H), 3.53 (s, 2H), 2.26 (m, 1H), 1.02 (d, 3H),0.95 (d, 3H ).

e) Iodomethyl 2-(N-CBZ-L-valyloxy)phenylacetate

Chloromethyl 2-(N-CBZ-L-valyloxy)phenylacetate is treated with NaI andpurified as described in the Examples above to yield the title compound.

EXAMPLE A-I-19 Iodomethyl 4-(N-CBZ-L-valyloxyxy)phenylacetate

a) 4-Methoxybenzyl 4-hydroxyphenylacetate

Prepared from 4-hydroxyphenylacetic acid (10 g, 65.7 mmol) in 70% yieldby the same procedure as for Example A-I-18 a) above, but wherein thesolvent for the recrystallization was changed to hexane-ether.

¹H NMR (CDCl₃ 45° C.): 7.25 (d, 2H), 7.12 (d, 2H), 6.87 (d, 2H), 6.76(d, 2H), 5.06 (s, 2H), 3.80 (s, 3H), 3.56 (s, 2H).

b) 4-Methoxybenzyl 4-(N-CBz-L-valyloxy)phenylacetate

Prepared from 4-methoxybenzyl 4-hydroxyphenylacetate (3 g, 11 mmol) bythe same procedure as for Example A-I-18b) in 87% yield. Solvent forchromatography: ethyl acetate-hexane, 1:2

¹H NMR (CDCl₃ 45° C.): 7.38-7.22 (m, 9H), 6.9 (d, 2H), 6.86 (d, 2H), 5.3(br s, 1H), 5.14 (s, 2H), 5.06 (s, 2H), 3.80 (s, 3H), 3.62 (s, 2H), 2.35(m, 1H), 1.08 (d, 3H), 1.02 (d,3H).

c) 4-(N-CBZ-L-valyloxy)phenylacetic acid

Prepared in 82% yield from 4-methoxybenzyl4-(N-CBz-L-valyloxy)phenylacetate (1.6 g, 288 mmol) by the proceduredescribed for Example A-I-18 c). Solvent for recrystallization:hexane-ether and a small amount of dichloromethane. The compound can beactivated and esterified to a drug or further modified as describedbelow.

¹H NMR (CDCl₃ 45° C.): 7.36-7.27 (m, 7H), 7.02 (d, 2H), 5.25 (d, 1H),5.14 (s, 2H), 4.52 (m, 1H), 3.64 (s, 2H), 2.3 (m, 1H), 1.08 (d, 3H),1.02 (d, 3H).

d) Chloromethyl 4-(N-CBZ-L-valyloxy)phenylacetate

Prepared from 4-(N-CBZ-L-valyloxy)phenylacetic acid (3 g, 7.8 mmol) in26% yield by the same procedure as described for Example A-I-18 d).Solvent for chromatography: hexane-ether, 3:2.

¹H NMR (CDCl₃ 45° C.): 7.30-6.95 (m, 4H), 5.51 (s, 2H), 5.15 (br s, 1H),5.07 (s, 2H), 4.43 (m, 1H), 3.60 (s, 2H) 2.25 (m, 1H), 1.00 (d, 3H),0.95 (d, 3H).

e) Iodomethyl 4-(N-CBZ-L-valyloxy)phenylacetate

Chloromethyl 4-(N-CBZ-L-valyloxy)phenylacetate (0.83 g, 1.9 mmol) andsodium iodide (1.15 g, 7.6 mmol) were heated in acetonitril (45 ml) for5 h. The mixture was filtrated, the solvent removed, taken up indichloromethane and filtrated again. Evaporation and purification bychromatography (ether-hexane, 2:3) yielded the title product (0.8 g,80%).

¹H NMR (CDCl₃ 45° C.): 7.38-7.09 (m, 4H), 5.84 (s, 1H), 5.30 (br s, 1H),5.15 (s, 2H), 4.5 (m, 1H), 3.56 (s, 2H), 2.36 (m, 1H), 1.10 (d, 3H),1.00 (d, 3H).

EXAMPLE A-I-20 Iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoate

a) 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)-toluene

To a cooled solution of 4-methylphenylethanol-2 (5.0 g, 36.7 mmole),4-dimethylaminopyridine (0.98 g, 8 mmole) andN-benzyloxycarbonyl-L-valine (10.05 g, 40 mmole) in dichloromethane (120ml) was added dicyclohexyl-carbodiimide (9.1 g, 44 mmole) and themixture was stirred overnight at room temperature. The mixture wascooled and the urethane was filtered. The solution was evaporated underreduced pressure and ethyl acetate (250 ml) was added. The organic phasewas washed twice with 5% acetic acid, 5% sodium hydrogencarbonate andwater. The organic phase was dried with sodium sulfate and evaporatedunder reduced pressure. The product was isolated by silica gel columnchromatography with toluene/acetone. Yield: 13.3 g=97%

¹H-NMR (CDCl₃) 0.86 (m, 6H) 2.12 (m, 1H) 2.32 (s, 3H) 2.91 (m, 2H) 4.32(m, 3H) 5,12 (s, 2H) 5.24 (d, 2H) 7.10-7.36 (m, 9H)

b) 4(2-N-benzyloxycarbonyl-L-valyloxyethyl)-benzoic acid.

To a cooled mixture of chromic anhydride (7,55 g, 75 mmole) in aceticacid (100 ml) was added dropwise a solution of4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)-toluene (9.3 g, 25.1 mmole) inacetone (50 ml). The mixture was stirred at room temperature for 3 daysand reduced to about 100 ml. 600 ml 10% sodium chloride solution wasadded and the mixture was extracted four times with ethyl acetate. Theorganic phase was washed with brine and dried with sodium sulfate. Thesolution was evaporated under reduced pressure and the product wasisolated by silica gel column chromatography withdichloromethane/methanol. Yield: 2,1 g=21%. The product can be activatedand esterified directly onto a drug or further modified as describedbelow.

¹H-NMR (CDCl₃) 0.79 (d, 3H) 0.90 (d, 3H) 2.08 (m,1H) 3.04 (t, 2H) 4.28(d, d,1H) 4.39 (m, 2H) 5.11 (s, 2H) 5.26 (d, 1H) 7.34 (m, 7H) 8.04 (d,2H)

c) Chloromethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoate

To a solution of 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoic acid(2.0 g, 5.0 mmole) in 1,4-dioxane (20 ml) was added a 40% solution oftetrabutylammonium hydroxide (3.1 g, 4.75 mmole) and the mixture wasstirred 2 hours at room temperature. The mixture was evaporated underreduced pressure and coevaporated two times with 1,4-dioxane and twotimes with toluene. The dried product was dissolved in dichloromethane(10 ml) and iodochloromethane (13.2 g, 75 mmole) was added. The solutionwas stirred overnight at room temperature and evaporated under reducedpressure. About 50 ml ethyl acetate were added and the organic phasewashed twice with water, dried with sodium sulfate and evaporated underreduced pressure. The product was isolated by silica gel columnchromatography. Yield: 0.5 g=23%

¹H-NMR (CDCl₃) 0.79 (d, 3H) 0.92 (d, 3H) 2.12 (m, 1H) 3.03 (t, 2H) 4.28(d, d, 1H) 5.10 (s, 2H) 5.22 (d, 1H) 5.94 (s, 2H) 7.34 (m, 7H) 8.02 (d,2H)

d) Iodomethyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoate

To a solution of chloromethyl4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoate (0.5 g, 1.11 mmole).In dry acetone (10 ml) was added sodium iodide (0.75 g, 5.0 mmole) andthe mixture was stirred overnight at room temperature. The mixture wasevaporated under reduced pressure and extracted with ethyl actate/water.The organic phase was washed with a 5% sodium thiosulfate solution,dried with sodium sulfate and evaporated under reduced pressure. Yield:0.53 g=88%.

¹H-NMR (CDCl₃) 0.88 (d, 3H) 0.90 (d, 3H) 2.08 (m, 1H) 3.02 (t, 2H) 4.28(d, d, 1H) 4.38 (m, 2H) 5.10 (s, 2H) 5.22 (d, 1H) 6.15 (s, 2H) 7.35(m,7H) 7.98 (d, 2H)

EXAMPLE A-I-21 Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)2-methyl propionate

a) 4-methoxybenzyl 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)-2-methylpropionate

To a cooled solution of 4-methoxybenzyl 2-(hydroxymethyl)-2-methylpropionate (6.0 g, 25 mmole), 4-dimethylaminopyridine (0.61 g, 5 mmole)and N-benzyloxycarbonyl-L-isoleucine (6.90 g, 26 mmole) indichloromethane (100 ml) was added dicyclohexyl-carbodiimide (6.2 g, 30mmole) and the mixture was stirred overnight at room temperature. Themixture was cooled and the urethane was filtered. The solution wasevaporated and 200 ml ethyl acetate was added, The organic phase waswashed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water.The organic phase was dried with sodium sulfate and evaporated underreduced pressure. The product was isolated by silica gel columnchromatography with toluene/acetone. Yield: 11.7 g=96%.

¹H-NMR (CDCl₃) 0.88 (m, 6H) 1.22 (m, 8H) 1.82 (m, 1H) 3.80 (s, 3H) 4.18(d, d, 2H) 4.32 (d, d, 1H) 5.12 (m, 5H) 6.90 (d, 2H) 7.26 (m, 7H)

2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)-2-methyl)propionic acid.

To a solution of 4-methoxybenzyl2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)-2-methyl propionate (11.0g, 22.6 mmole) in 100 ml dichloromethane was added trifluoroacetic acid(15 ml) and the mixture was stirred overnight at room temperature. Thesolution was evaporated under reduced pressure and coevaporated twotimes with toluene. The residue was stirred 1 hour with 100 ml ethanoland the white solid was filtered (byproduct). The solution wasevaporated under reduced pressure and the product was isolated by silicagel column chromatography with hexane/ethyl acetate. Yield: 7.4 g=89%.The product can be activated and esterified directly to a drug, orfurther modified as described below.

¹H-NMR (CDCl₃) 0.90 (m, 6H) 1.26 (m, 8H) 1.88 (m, 1H) 4.12 (d, d, 2H)4.38 (d, d, 1H) 5.10 (s, 2H) 5.32 (d, 1H) 7.28 (m, 5H)

c) Chloromethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxy)-2-methylpropionate.

To a solution of 2-N-benzyloxycarbony-L-isoleucyloxymethyl)-2-methylpropionic acid (7.0 g, 19 mmole) in 80 ml 1,4-dioxane was added a 40%solution of tetrabutylammonium hydroxide (12.4 g, 19 mmole) and themixture was stirred 2 hours at room temperature. The mixture wasevaporated under reduced pressure and co-evaporated two times with1,4-dioxane and two times with toluene. The dried product was dissolvedin 25 ml dichloromethane and iodochloromethane (33.7 g, 190 mmole) wasadded. The solution was stirred overnight at room temperature andevaporated under reduced pressure. About 100 ml ethyl actate was addedand the organic phase washed twice with water, dried with sodium sulfateand evaporated under reduced pressure. The product was isolated bysilica gel column chromatography with toluene/acetone. Yield: 4.2=54%

¹H-NMR (CDCl₃) 0.94 (m, 6H) 1.26 (m, 8H) 1.90 (m, 1H) 4.15 (d, d, 2H)4.38 (d, d, 1H) 5.10 (s, 2H) 5.24 (d, 1H) 5.70 (s, 2H) 7.35 (m, 5H).

d) Iodomethyl 2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)-2-methylpropionate.

To a solution of chloromethyl2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)-2-methyl propionate (3.0 g,7.2 mmole) in 50 ml dry acetone was added sodium iodide (4.8 g, 32mmole) and the mixture was stirred overnight at room temperature. Themixture was evaporated under reduced pressure and extracted with ethylactate water. The organic phase was washed with a 5% sodium thiosulfatesolution, dried with sodium sulfate and evaporated under reducedpressure. Yield: 3.3 g=90%.

¹H-NMR (CDCl₃) 0.93 (m, 6H) 1.23 (m, 8H) 4.12 (m, 2H) 4.38 (d, d, 1H)5.10 (s, 2H) 5.26 (d, 1H) 5.92 (m, 2H) 5.35 (m, 5H)

EXAMPLE A-I-22 Iodomethyl4-(N-benzyloxycarbonyl-L-valyloxy)cyclohexanoate

a) 4-Methoxybenzyl 4-hydroxycyclohexanoate.

To a solution of ethyl 4-hydroxycyclohexanoate (8.61 g, 50 mmole) in 50ml ethanol was added a solution of potassium hydroxide 85% (3.63 g, 55mmole) and the mixture was stirred for 6 hours at 70° C. The mixture wasevaporated under reduced pressure, coevaporated two times withN,N-dimethylformamide and reduced to about 100 ml. 4-Methoxybenzylchloride (9.4 g, 60 mmole) was added and the mixture was stirred for 18hours at 60° C. The mixture was evaporated under reduced pressure and250 ml ethyl acetate was added. The organic phase was washed five timeswith water, dried with sodium sulfate and evaporated under reducedpressure. Yield: 13.2 g=100% (crude)

¹H-NMR (CDCl₃) 1.50-2.02 (m, 8H) 2.38 (m, 1H) 3.58-3.92 (m, 4H) 5.05 (d,2H) 6.89 (m, 2H) 7.27 (m, 2H)

b) 4-methoxybenzyl 4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate.

To a cooled solution of 4-methoxybenzyl 4-hydroxycyclohexanoate (7.5 g,28 mmole), 4-dimethylaminopyridine (0.73 g, 6 mmole) andN-benzyloxycarbonyl-L-valine (7.54 g, 30 mmole) in dichloromethane (90ml) was added dicylohexyl-carbodiimide (6.8 g, 33 mmole) and the mixturewas stirred for 2 days at room temperature. The mixture was cooled andthe urethane was filtered. The solution was evaporated and 250 ml ethylacetate was added. The organic phase was washed twice with 5% aceticacid, 5% sodium hydrogencarbonate and water. The organic phase was driedwith sodium sulfate and evaporated under reduced pressure. The productwas isolated by silica gel column chromatography with toluene/acetone.Yield: 13 g=93%

¹H-NMR (DMSO d-6) 0.88 (m, 6H) 1.56-2.12 (m, 10H) 3.72 (s, 3H) 3.90 (m,1H) 5.04 (d, 4H) 6.91 (d, 2H) 7.34 (m, 7H) 7.67 (d, 1H).

c) 4-(N-benzyloxycarbonyl-L-valyloxy) cyclohexanoic acid.

To a solution of 4-methoxybenzyl4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate (12 g, 24.1 mmole) indichloromethane (100 ml) was added trifluoroacetic acid (20 ml) and themixture was stirred for 3 hours at room temperature. The solution wasevaporated under reduced pressure and coevaporated two times withtoluene. The residue was stirred 1 hour with about 100 ml ethanol andthe white solid was filtered (byproduct). The solution was evaporatedunder reduced pressure and the product was isolated by silica gel columnchromatography with toluene/acetone. Yield: 6.8 g=74%. The product canbe activated and esterified directly to a drug or further modified asdescribed below.

¹H-NMR (CDCl₃) 0.91 (m, 6H) 1.52-2.54 (m, 1H) 4.28 (m, 1H) 4.82-5.08 (m,1H) 5.11 (s, 2H) 5.28 (d, 1H) 7.36 (m, 5H)

d) Chloromethyl 4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate.

To a solution of 4-(N-benzyloxycarbonyl-L-valyloxy)cyclohexanoic acid(6.6 g, 20 mmole) in 1,4-dioxane (70 ml) was added a 40% solution oftetrabutylammonium hydroxide (11.34 g, 17.5 mmole) and the mixture wasstirred 2 hours at room temperature. The mixture was evaporated underreduced pressure and co-evaporated two times with 1,4-dioxane and twotimes with toluene. The dried product was dissolved in 60 mldichloromethane and iodochloromethane (30.9 g, 175 mmole) was added. Thesolution was stirred for two days at room temperature and evaporatedunder reduced pressure. About 100 ml ethyl actate was added and theorganic phase washed twice with water, dried with sodium sulfate andevaporated under reduced pressure. The product was isolated by silicagel column chromatography with toluene/acetone. Yield: 4.1 g=55%.

¹H-NMR (CDCl₃) 0.92 (m, 6H) 1.54-2.58 (m, 10H) 4.32 (m, 1H) 4.78-5.08(m, 1H) 5.11 (s, 2H) 5.72 (d, 2H) 7.36 (m, 5H)

e) Iodomethyl 4-(N-benzyloxycarbonyl-L-valyloxy)cyclohexanoate.

To a solution of chloromethyl4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate (4.0 g, 9.4 mmole) indry acetone (50 ml) was added sodium iodide (6.3 g, 42 mmole) and themixture was stirred overnight at room temperature. The mixture wasevaporated under reduced pressure and extracted with ethyl actate water.The organic phase was washed with a 5% sodium thiosulfate solution,dried with sodium sulfate and evaporated under reduced pressure. Yield4.5 g=93%.

¹H-NMR (CDCl₃) 0.90 (m, 6H) 1.52-2.02 (m, 8H) 2.18 (m, 1H) 2.43 (m, 1H)4.30 (m, 1H) 4.76-5.08 (m, 1H) 5.11 (s, 2H) 5.26 (d, 1H) 5.91 (d, 2H)7.34 (m, 5H)

EXAMPLE A-I-23 Iodomethyl2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl butyrate

a) 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethylbutan-1-ol.

To a cooled solution of 2-ethyl-2-hydroxymethyl-butan-1-ol (33.1 g, 250mmole), 4-dimethylaminopyridine (1.22 g, 10 mmole) andN-benzyloxycarbonyl-L-valine (12.6 g, 50 mmole) in 350 mldichloromethane was added dropwise a solution ofdicyclohexyl-carbodiimide (12.4 g, 60 mmole) in 50 ml dichlorometane.The mixture was stirred 2 days at room temperature and cooled. Theurethane was filtered and the solution evaporated under reducedpressure. 350 ml ethyl acetate was added and the organic phase waswashed twice with 5% acetic acid, 5% sodium-hydrogencarbonate and water.The organic phase was dried with sodium sulfat and evaporated underreduced pressure. The product was isolated by silica gel columnchromatography with dichloromethane/methanol. Yield: 16.4 g=90%.

¹H-NMR (CDCl₃) 0.92 (m, 12H) 1.26 (m, 4M) 2.14 (m, 1H) 3.36 (d, 2H) 4.01(d, 2H) 4.38 (d, d, 1H) 4.65 (br, 1H) 5.11 (s, 2H) 5.30 (d, 1H) 7.35 (m,5H)

c) 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl-butyric acid.

To a cooled mixture of chromic anhydride (8.5 g, 85,2 mmole) in 100 mlacetic acid was added dropwise a solution of2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl-butan-1-ol (10.4 g,28.4 mmole) in 50 ml acetone and the mixture was stirred 24 hours atroom temperature. The mixture was added to 1000 ml 10% sodium chloridesolution and extracted four times with ethyl acetate. The organic phasewas washed twice with brine, dried with sodium sulfate and evaporatedunder reduced pressure. The product was isolated by silica gel columnchromatography with hexane/ethyl acetate. Yield: 7 g=65%. The productcan be activated and esterified directly to a drug or further modifiedas described below.

¹H-NMR (CDCl₃) 0.88 (m, 12H) 1.67 (m, 4H) 2.14 (m, 1H) 4.26 (m, 3H) 5.10(s, 2H) 5.30 (d, 2H) 7.34 (m, 5H)

d) Chloromethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl-2-ethylbutyrate.

To a solution of 2-(N-benzyloxycarbony-L-valyloxymethyl)-2-ethyl-butyricacid (7.2 g, 18,9 mmole) in 1,4-dioxane (80 ml) was added a 40% solutionof tetrabutylammonium hydroxide (12.26 g, 18.9 mmole) and the mixturewas stirred 2 hours at room temperature. The mixture was evaporatedunder reduced pressure and co-evaporated once with 1,4-dioxane and twotimes with toluene. The dried product was dissolved in 30 mldichloromethane and iodochloromethane (49.4 g, 280 mmole) was added. Thesolution was stirred for two days at room temperature and evaporatedunder reduced pressure. About 100 ml ethyl actate were added and theorganic phase washed twice with water, dried with sodium sulfate andevaporated under reduced pressure. The product was isolated by silicagel column chromatography. Yield: 5.2 g=63%.

¹H-NMR (CDCl₃) 0.92 (m, 12H) 1.68 (m, 4H) 2.18 (m, 1H) 4.28 (m, 3H) 5.10(s, 2H) 5.24 (d, 1H) 5.72 (s, 2H) 7.35 (m, 5H).

e) Iodomethyl 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl butyrate.

To a solution of chloromethyl2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl butyrate (5.0 g, 11.7mmole) in dry acetone (60 ml) was added sodium iodide (7.5 g, 50 mmole)and the mixture was stirred overnight at room temperature. The mixturewas evaporated under reduced pressure and extracted with ethyl actatewater. The organic phase was washed with a 5% sodium thiosulfatesolution, dried with sodium sulfate and evaporated under reducedpressure. Yield: 5.4 g=90%.

¹H-NMR (CDCl₃) 0.92 (m, 12H) 1.65 (m, 4H) 2.18 (m, 1H) 4.28 (m, 3H) 5.10(s, 2H) 5.22 (d, 1H) 5.92 (s, 2H) 7.36 (m, 5H)

EXAMPLE A-I-242-(N-(iodomethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy-propane

a)2-(N-tert-butyloxycarbonylamino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)propane.

To a cooled solution of2-(N-(tert-butyloxycarbonyl)-amino)-2-methylpropan-1-ol (J. Am. Chem.Soc 113 (1991) p 8883) (4.73 g, 25 mmole), 4-dimethylamino-pyridine(0.61 g, 5 mmole) and N-benzyloxycarbonyl-L-valine (6.28 g, 25 mmole) indichloromethane (70 ml) was added dicyclohexyl-carbodiimide (6.19 g, 30mmole) and the mixture was stirred 2 days at room temperature. Themixture was cooled, the urethane was filtered and the solutionevaporated under reduced pressure. Ethyl acetate (200 ml) was added andthe organic phase was washed twice with 5% acetic acid, 5% sodiumhydrogencarbonate and water. The organic phase was dried with sodiumsulfate and evaporated under reduced pressure. The product was isolatedby silica gel column chromatography with hexane/ethyl acetate. Yield:10.2 g=96%.

¹H-NMR (CDCl₃) 0.96 (m, 6H) 1.32 (s, 6H) 1.42 (s, 9H) 2.20 (m, 1H)4.08-4.58 (m, 3H) 5.11 (s, 2H) 5.32 (d, 1H) 7.36 (m, 5H)

b) 2-amino-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane.

To a solution of2-(N-(tert-butyloxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane(10 g, 23 mmole) in dichloromethane (150 ml) was added trifluoroaceticacid (30 ml) and the mixture was stirred for 1 hour at room temperature.The solution was evaporated under reduced pressure and 10% sodiumcarbonate solution was added. The product was extracted four times withdichloromethane, dried with sodium sulfate and evaporated under reducedpressure. The product was isolated by silica gel column chromatographywith dichloromethane/methanol. Yield: 3.0 g=40% (crude)

c)2-(N-(chloromethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane.

To a solution of2-amino-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane (2.9 g, 9mmole) and pyridine (2 ml) in dichloromethane (50 ml) was addedchloromethyl chloroformate(1.55 g, 12 mmole) and the mixture was stirredfor 3 hours at room temperature. The mixture was evaporated underreduced pressure and ethyl acetate was added. The organic phase waswashed with water, dried with sodium sulfate and evaporated underreduced pressure. The product was isolated by silica gel columnchromatography with hexane/ethyl acetate. Yield: 1.1 g=29%.

¹H-NMR (CDCl₃) 0.92 (m, 6H) 1.35 (s, 6H) 2.10 (m, 1H) 3.87 (m, 1H) 4.36(m, 2H) 5.11 (s, 2H) 5.30 (d, 1H) 5.70 (s, 2H) 5.78 (s, 1H) 7.35 (m,5H).

d)2-N-(iodomethoxycarbonyl)-amino)-2-methyl)-1-(N-benzyloxycarbonyl-L-valyloxy)-propane.

To a solution of2-(N-(chloromethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)propane(1.05 g, 2.53 mmole) in dry acetone (20 ml) was added sodium iodide (1.8g, 12 mmole) and the mixture was stirred for 36 hours at roomtemperature. The mixture was evaporated under reduced pressure and ethylacetate and water were added. The organic phase was washed with 10%sodium thiosulfate solution and water. The organic phase was dried withsodium sulfate and evaporated under reduced pressure. Yield 1.04 g=81%.

¹H-NMR (CDCl₃) 0.92 (m, 6H) 1.35 (s, 6H) 2.10 (m, 1H) 3.88 (m, 1H) 4.35(m, 2H) 5.11 (s, 2H) 5.32 (d, 1H) 5.82 (s, 1H) 5.91 (s, 2H) 7.35 (m, 5H)

EXAMPLE A-I-251-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acidiodomethyl ester

a) 6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester

To a solution of 6-hydroxynicotinic acid (4.87 g, 35 mmol) in DMF (100mL) at room temperature, was added potassium tert-butoxide (3.93 g, 35mmol). The reaction mixture was stirred at 60° C. for 1 h.4-Methoxybenzylchloride (8.30 g, 53 mmol) was added and the reactionmixture was stirred at 60° C. for 4 h. The DMF was evaporated undervacuum, the residue was dissolved in ether (200 mL) and washed withwater (3×100 mL). The organic phase was dried with Na₂SO₄ and evaporatedto give 4.41 g of 6-oxo-1,6-dihydro-pyridine-3-carboxylic acid4-methoxybenzyl ester.

¹H-NMR (CDCl₃): 8.20 (d, J=2.5 Hz, 1H), 8,01 (dd, J=9.5, 2.5 Hz, 1H),7.33 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 6.54 (d, J=9.5 Hz, 1H),5.22 (s, 2H), 3.81 (s, 3H).

b) 1-(2-Hydroxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid4-methoxybenzyl ester

To a solution of 6-oxo-1,6-dihydro-pyridine-3-carboxylic acid4-methoxybenzyl ester (4.41 g, 17 mmol) and K₂CO₃ (2.58 g, 18.7 mmol) inDMF (100 mL) at room temperature, was added 2-bromoethanol (2.02 g, 16.2mmol). The reaction mixture was stirred at 80° C. for 30 h, whereuponthe DMF was evaporated under vacuum. The crude product was columnchromatographed (silica gel, 2→5% MeOH in CH₂Cl₂), to give 3.91 g of1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid4-methoxybenzyl ester.

¹H-NMR (CDCl₃): 8.26 (d, J=2.5 Hz, 1H), 7.85 (dd, J=9.5, 2.5 Hz, 1H),7.34 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 6.47 (d, J=9.5 Hz, 1H),5.21 (s, 2H), 4.09 (t, 2H), 3.90 (m, 2H), 3.81 (s, 3H), 3.64 (br s, 1H).

c) 1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid 4-methoxybenzyl ester

To a mixture of DCC (5.06 g, 24.5 mmol), DMAP (318 mg, 2.6 mmol) andN-CBz-L-valine (6.48 g, 25.8 mmol) in CH₂Cl₂ (200 mL) at 0° C., wasadded dropwise a solution of1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid4-methoxybenzyl ester (6.40 g, 24 mmol) in CH₂Cl₂ (200 mL). After 1 h at0° C., the temperature of the reaction mixture was allowed to assumeroom temperature and then the mixture was stirred for 5 h at roomtemperature. The mixture was filtered through a glass filter and thesolvent was removed under reduced pressure. The crude product was columnchromatographed (silica gel, 2→5% MeOH in CH₂Cl₂), to give 6.81 g1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid4-methoxybenzyl ester.

¹H-NMR (CDCl₃): 8.15 (d, J=2.5 Hz, 1H), 7.83 (dd, J=9.6, 2.5 Hz, 1H),7.37-7.25 (m, 7H), 6.88 (d, 2H), 6.49 (d, J=9.6 Hz, 1H), 5.35 (d, 1H),5.21 (s, 2H), 5.06 (s, 2H), 4.48-4.05 (m, 5H), 3.78 (s, 3H), 2.10-1.98(m, 1H), 0.85 (d, 3H), 0.75 (d, 3H).

d) 1-(2-N-CBz-L-valyloxyethyl)-2-pyridone-5-carboxylic acid

To a solution of1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid4-methoxybenzyl ester (6.46 g, 12 mmol) in CH₂Cl₂ (85 mL) at roomtemperature, was added trifluoroacetic acid (15 mL). After 1 h at roomtemperature, the reaction mixture was concentrated under reducedpressure. The crude product was column chromatographed (silica gel, 3→6%MeOH in CH₂Cl₂), to give 4.91 g1-(2-N-CBz-L-valyloxyethyl)-2-pyridone-5-carboxylic acid. The productcan be activated and esterified direct to a drug or further modified asdescribed below.

¹H-NMR (CDCl₃): 12.15 (br s, 1H), 8.29 (d, J=2.2 Hz, 1H), 7.93 (dd,J=9.5, 2.2 Hz, 1H), 7.31 (m, 5H), 6.69 (d, J=9.5 Hz, 1H), 55.3 (d, 1H),5.07 (s, 2H), 4.52-4.05 (m, 5H), 2.20-2.00 (m, 1H), 0.90 (d, 3H), 0.81(d, 3H).

e) 1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid chloromethyl ester

To a solution of 1-(2-N-CBz-L-valyloxyethyl)-2-pyridone-5-carboxylicacid (4.91 g, 11.8 mmol) in dioxane (200 mL), was added dropwise a 40%aqueous solution of tetrabutylammonium hydroxide (7.65 g). Afterstirring for 5 min, the solution was evaporated to dryness throughco-evaporation with dioxane and toluene. The residue was dissolved indichloromethane (200 mL) and then chloroiodomethane (8.74 mL, 120 mmol)was added and the solution was stirred for 12 h at room temperature. Thesolution was concentrated under reduced pressure and the residue wasshaken with hexane/ethyl acetate (1:1 v/v, 200 mL). The yellowcrystalline solid was filtered off and the filtrate was washed withaqueous solution of sodium thiosulfate (0.1 M) and the filtered throughanhydrous sodium sulfate and evaporated to dryness. The residue wascolumn chromatographed (silica gel, 2-4% MeOH in CH₂Cl₃), to give 1.80 gof 1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid chloromethyl ester.

¹H-NMR (CDCl₃): 8.24 (d, J=2.5 Hz, 1H), 7.83 (dd, J=9.6, 2.5 Hz, 1H),7.33 (m, 5H), 6.54 (d, J=9.6 Hz, 1H), 5.86 (s, 2H), 5.34 (d, 1H), 5.09(s, 2H), 4.56-4.08 (m, 5H), 2.20-2.00 (m, 1H), 0.92 (d, 3H), 0.83 (d,3H).

f) 1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid iodomethyl ester

To a solution of1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acidchloromethyl ester (1.80 g, 3.87 mmol) in acetonitrile (30 mL), wasadded sodium iodide (2.32 g, 15.5 mmol). The solution was stirred for 4h at 60° C. The resulting suspension was filtered and the filtrate wasevaporated. The residue was dissolved in CH₂Cl₂ and washed with aqueoussodium thiosulfate (0.1 M). The organic phase was dried (Na₂SO₄) andconcentrated under reduced pressure. The crude product was columnchromatographed (silica gel, 1% MeOH in CH₂Cl₂), to give 2.04 g1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acidiodomethyl ester.

¹H-NMR (CDCl₃): 8.19 (d, J=2.5 Hz, 1H), 7.79 (dd, J=9.6, 2.5 Hz, 1H),7.32 (m, 5H), 6.52 (d, J=9.6 Hz, 1H), 6.04 (s, 2H), 5.38 (d, 1H), 5.07(s, 2H), 4.54-4.06 (m, 5H), 2.20-2.00 (m, 1H), 0.91 (d, 3H), 0.81 (d,3H).

EXAMPLE A-I-26 Iodomethyl5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furoate

(a) 5-[(N-Benzyloxycarbonyl-L-valyloxy)methyl]-2-furaldehyde

A solution of 5-(hydroxymethyl)-2-furaldehyde (1.00 g, 7.69 mmol) in 5mL dry CH₂Cl₂ was added to a mixture of N-benzyloxycarbonyl-L-valine(2.40 g, 9.57 mmol), N,N′-dicyclohexylcarbodiimide (2.00 g, 9.69 mmol),and 4-dimethyl-aminopyridine (117 mg, 0.96 mmol) in 45 mL CH₂Cl₂. Afterstirring overnight, the reaction slurry was filtered, concentrated undervacuum, and subjected to flash column chromatography (silica, 2/1petroleum ether-ethyl acetate to give the valine ester (quantitativeyield).

¹H NMR (250 MHz, CDCl₃) δ 0.86 and 0.94 (2d, 3H each, J=6.9 Hz), 2.16(m, 1H), 4.34 (dd, 1H, J=9.0, 4.7 Hz), 5.10 (s, 2H), 5.13-5.27 (m, 3H),6.59 (d, 1H, J=3.4 Hz), 7.19 (d, 1H, J=3.5 Hz), 7.35 (s, 5H), 9.63 (s,1H).

(b) 5-[(N-Benzyloxycarbonyl-L-valyloxy)methyl]-2-furoic acid

A solution of NaClO₂ (2.8 mmol) in 3 mL water was added dropwise to astirred solution of5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furaldehyde (798 mg, 2.22mmol) from step (a) in 3 mL MeCN, with cooling in an ice bath. After 2.5h, the ice bath was removed, 2 mL more MeCN was added, and the two-phaseliquid reaction mixture was stirred at room temperature for 25 h. Thereaction mixture was diluted with water, made basic with saturatedNaHCO₃, and extracted with ethyl acetate (3×50 mL). The separatedaqueous solution was acidified to pH 2 with 5% aqueous HCl and extractedwith ethyl acetate (3×50 mL). This second ethyl acetate solution waswashed with brine, dried over anhydrous Na₂SO₄, and evaporated todryness under vacuum to give the carboxylic acid (287 mg, 34%) which wasused in the next step without further purification. The compound can beactivated and esterified direct to a drug or further modified asdescribed below.

¹H NMR (250 MHz, CDCl₃) δ 0.84 and 0.93 (2d, 3H each, J=6.8 Hz), 2.15(m, 1H), 4.35 (dd, 1H, J=9.0, 4.7 Hz), 5.10-5.24 (m, 4H), 5.44 (d, 1H,J=9.0 Hz), 6.54 (d, 1H, J=3.3 Hz), 7.23 (d, 1H, J=3.3 Hz), 7.33 (s, 5H),11.05 (br s, 1H).

(c) Chloromethyl 5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furoate

Tetrabutylammonium hydroxide (40 wt. % solution in water, 0.55 mL, 0.84mmol) was added to the carboxylic acid (286 mg, 0.76 mmol) from step (b)in 5 mL dioxane. The yellow solution was concentrated under vacuum,coevaporating several times with dioxane, toluene, and, lastly, CH₂Cl₂.The residue was charged with 10 mL dry CH₂Cl₂ and chloroiodomethane(0.55 mL, 7.55 mmol) was added. After stirring for 20.5 h, the reactionmixture was concentrated and subjected to flash column chromatography(silica, 2/1 petroleum ether—ethyl acetate) to give the chloromethylester (137 mg, 42%).

¹H NMR (250 MHz, CDCl₃) δ 0.85 and 0.93 (2d, 3H each, J=6.9 Hz), 2.14(m, 1H), 4.33 (dd, 1H, J=9.0, 4.8 Hz), 5.09-5.22 (m, 4H), 5.37 (d, 1H,J=8.9 Hz), 5.88 (s, 2H), 6.53 (d, 1H, J=3.4 Hz), 7.23 (d, 1H, J=3.5 Hz),7.32 (s, 5H).

(d) Iodomethyl 5-[(N-benzyloxycarbonyl-L-valyloxy)methyl]-2-furoate

All of the chloromethyl ester (137 mg, 0.32 mmol) from step (c) wasrefluxed with NaI (195 mg, 1.3 mmol) in 3.2 mL dry MeCN at 70° C. for 4h. The solvent was removed under vacuum and the residue was subjected toflash column chromatography (silica, 3/1 petroleum ether-ethyl acetate)to give the iodomethyl ester (152 mg, 92%).

¹H NMR (250 MHz, CDCl₃) δ 0.84 and 0.93 (2d, 3H each, J=6.8 Hz), 2.16(m, 1H), 4.33 (dd, 1H, J=9.1, 4.7 Hz), 5.09-5.21 (m, 4H), 5.36 (d, 1H,J=9.1 Hz), 6.08 (s, 2H), 6.52 (d, 1H, J=3.4 Hz), 7.19 (d, 1H, J=3.5 Hz),7.33 (s, 5H).

EXAMPLE A-I-27 4-(2-N-benzyloxycarbonyl-L-valyloxyethyl)benzoic acid

a) 4-Methoxybenzyl 4-(2-hydroxyethoxy)benzoate

To a solution of 4methoxybenzyl 4-hydroxybenzoate (7.0 g, 27 mmole) indry N,N-dimethylformamide (50 ml) was added potassium carbonate (4.15 g,30 mmole) and 2-bromoethanol. The mixture was stirred 48 hours at 80°C., evaporated under reduced pressure and ethyl acetate and water wereadded. The organic phase was washed five times with water and dried withsodium sulfate. The solution was evaporated under reduced pressure andthe product was isolated by silica gel column chromatography withhexane/ethyl acetate.

Yield: 6.8 g=83%. ¹H-NMR (CDCl₃) 3.81 (s, 3H) 4.00 (m, 2H) 4.12 (m, 2H)5.26 (s, 2H) 6.90 (m, 4H) 7.38 (d, 2H) 8.00 (d, 2H)

b) 4-methoxybenzyl 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy)benzoate.

To a solution of 4-methoxybenzyl 4-(2-hydroxyethoxy)benzoate (6.6 g,21.8 mmole), 4-dimethylaminopyridine (0.61 g, 5 mmole) andN-benzyloxycarbonyl-L-valine (6.3 g, 25 mmole) in dichloromethane (80ml) was added dicyclohexyl-carbodiimide (5.2 g, 25 mmole) and themixture was stirred overnight at room temperature. The mixture wascooled and the urethane was filtered. The solution was evaporated andethyl acetate (200 ml) was added. The organic phase was washed twicewith 5% acetic acid, 5% sodium hydrogencarbonate and water. The organicphase was dried with sodium sulfate and evaporated under reducedpressure. The product was isolated by silica gel column chromatographywith dichloromethane/methanol. Yield: 10.6 g=90%

¹H-NMR (CDCl₃) 0.90 (m, 6H) 2.18 (m, 1H) 3.82 (s, 3H) 4.14-4.64 (m, 5H)5.10 (s, 2H) 5.27 (s, 2H) 6.90 (m, 4H) 7.34 (m, 7H) 7.99 (d, 2H)

c) 4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy)-benzoic acid.

To a solution of 4-methoxybenzyl4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy) benzoate (10.2 g, 19.04mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (20ml) and the mixture was stirred 3 hours at room temperature. Thesolution was evaporated under reduced pressure and co-evaporated twotimes with toluene. The product was isolated by silica gel columnchromatography. Yield: 6.9 g=87%. The product may be activated andesterified direct to a drug or converted to iodomethyl4-(2-N-benzyloxycarbonyl-L-valyloxyethoxy)-benzoic acid as describedabove, that is by treatment with a base, chloroiodomethane, separationand then treatment with NaI.

¹H-NMR (CDCl₃) 0.94 (m, 6H) 2.18 (m, 1H) 4.22-4.68 (m, 5H) 5.10 (s, 2H)6.94 (d, 2H) 7.35 (m, 5H) 8.05 (d, 2H)

EXAMPLE 12-(stearoyloxyethyl)-2-(N-(fluorenylmethoxycarbonyl)-L-valyloxymethyl)-propionicacid

To a solution of 2,2-bis(hydroxymethyl)propionic acid (28.16 g, 210mmole) in water (50 ml), was added potassium hydroxide (11.78 g, 210mmole). After 5 min, the solution was evaporated in vacuo and theresidue was coevaporated with dry DMF for three times. The residue wasthen dissolved in DMF (500 ml), and to the solution was added benzylbromide (3.57 ml, 30 ml). After stirring for 30 min, the reactionmixture was filtered through the Celite, poured into sodium hydrogencarbonate aqueous solution and extracted with dichloromethane. Theorganic phase was collected and then washed with sodium hydrogencarbonated aqueous solution. It was then evaporated in vacuo to givebenzyl 2,2-bis(hydroxymethyl)propionate (4.37 g).

¹H-NMR (CDCl₃): 7.35 (s, 5H), 5.20 (d, 2H), 3.91-3.71 (m, 4H), 1.10 (s,3H).

To a solution of benzyl 2,2-bishydroxymethyl)propionate (4.37 g, 19.5mmole) in pyridine (58 ml) was added dropwise stearoyl chloride (4.13 g,13.6 mmole) in dichloromethane over 40 min. The reaction was then keptfor 16 hr and then poured into sodium hydrogen carbonate aqueoussolution and extracted with dichloromethane. The organic phase wascollected and evaporated in vacuo. The productbenzyl-2-(hydroxymethyl)-2-(stearoyloxymethyl)propionate was isolated bysilica gel column chromatography (1.97 g)

¹H-NMR (CDCl₃): 7.34 (s, 5H), 5.17 (d, 2H), 4.28 (dd, 2H) 3.69 (dd, 2H),2.24 (t, 2H), 1.57 (m, 2H, 1.25 (s, 28H, 1.22 (s, 3H), 0.87 (t, 3H).

Benzyl-2-(hydroxymethyl)-2-(stearoyloxymethyl)propionate (1.86 g, 3.8mmole) was dissolved in pyridine (30 ml). To the solution were addedtoluenesulfonic acid (73 mg, 0.39 mmole),N-fluorenylmethoxycarbonyl-L-valine (3.94 g, 11.6 mmole), and DCC (3.58g, 17.4 mmole). The reaction was kept at 4° C. for 16 hr and thenfiltered trough Celite. The filtrate was poured into sodium hydrogencarbonate aqueous solution and extracted with dichloromethane. Theorganic phase was collected and evaporated in vacuo. The product,benzyl-2-(N-fluorenyl-methoxycarbonyl)-L-valyloxymethyl)-2-(stearoyloxymethyl)propionate,was isolated by silica gel columy chromatography. Yield: 2.38 g.

¹H-NMR (CDCl₃): 7.78-7.25 (m, 13H), 5.29 (m, 1H), 5.15 (d, 2H),4.38-4.23 (m, 7H), 2.19 (t, 2H), 2.10 (m, 1H), 1.55 (m, 2H), 1.24 (m,31H), 0.94-0.83 (m, 9H).

To the solution of benzyl2-(N-(fluorenylmethoxycarbonyl)-L-valyloxymethyl)-2-(stearoyloxymethyl)propionate (1.86 g, 3.8 mmole) in a mixed solvent of THF/methanol (16ml/8 ml) were added ammonium formate (376 mg, 6 mmole), formic acid(1.87 ml), and palladium black (40 mg). The reaction was kept at roomtemperature for 16 hr, and then filtered through Celite. Afterevaporation, the product was isolated by silica gel columnchromatography. Yield: 1.05 g.

EXAMPLE 2 1-O-stearoyl-2-O-(N-CBz-L-valyl)glycerol

a) Preparation of 1-O-stearoylglycerol

To a mixture of glycerol (30 g, 326 mmol) and pyridine (25 ml) dissolvedin DMF (300 ml) was added dropwise stearoyl chloride (10 g, 33 mmol)dissolved in DMF 100 ml9. The mixture was cooled on an ice bath untiladdition was complete, whereupon the reaction was maintained under an N₂atmosphere overnight. After 15 hours CH₂CL₂ (300 ml) and saturatedNaHCO3 (aq) was added. The phases were separated and the organic phasewashed with water (50 ml) and dried with Na₂SO₄.

The solvent and any pyridine were evaporated under vacuum. The crudeproduct was chromatographed on a silica column (CH₂Cl₂-MeOH, 20:1) andrecrystallised (CH₂Cl₂-ether) to yield around 7 grams.

b) Preparation of Pixyl Chloride

Acetyl chloride (150 ml, 2.1 mol) is added to a magnetically stirredsuspension of 9-hydroxy-9-phenylxanthene (20 g 72 mmol) in benzene (100ml). An homogenous deep red solution is obtained. The solution isstirred for 30 min. at 20° C. The volatiles are removed under reducedpressure. Excess AcCl is neutralised by careful addition to ethanol. Theresidue is coevaporated with toluene (2×30 ml) and with cyclohexane(2×30 ml) to obtain a crystalline residue which is stored airtight.Pixyl chloride is alternatively available from Aldrich.

c) Preparation of 1-O-stearoyl, 3-O-pixylglycerol

The product from a) above (2.28 g) and pyridine (25 ml) were mixed andheated until dissolved. After cooling in an icebath pixyl chloride (1.92g) from step b) was added. The mixture was maintained under agitationand an argon atmoshere in an icebath for half an hour and then at roomtemperature for 1.5 h. The pyridine was evaporated under vacuum, theresidue dissolved in CH₂Cl₂ (70 ml) and washed with 0.5 M citricacid toremove remaining pyridine. The residue was dried with Na₂SO₄ evaporatedand chromatographed (ether-hexane 1.3) to give 1.25 g pure product witha TLC R_(f) around 0.2.

d) Preparation of 1-O-stearoyl, 2-O-(N-CBz-L-valyl), 3-O-pixylglycerol

The product of step c) (237 mg, 0.39 mmol), CBz-L-valine (116 mg, 0.46mmol), DCC (96 mg, 0.46 mmol) and DMAP (4.7 mg, 0.04 mmol) weredissolved in CH₂Cl₂ (4 ml). The mixture was maintained under agitationin a nitrogen atmosphere overnight. After 18 hours the mixture wasfiltered through a glass filter and chromatographed on a silica gelcolumn (ether-hexane 1:4) to yield 230 mg with a TLC R_(f) of 0.2

e) Preparation of 1-O-stearoyl-2-O-(N-CBz-L-valyl)glycerol

The pixyl group in the product of step d) was removed by selectivedeprotection by the method described in Example 3, step d to yield thetitle compound.

¹H-NMR (CDCl3): δ 7.35 (m, 5H), 5.3-4.9 (m, 4H), 4.35-4.25 (m, 3H),3.8-3.6 (m, 2H), 2.31-2.25 (m, 2H), 2.20-2.10 (m, 1H), 1.60 (m, 2H),1.02-0.86 (m, 9H).

EXAMPLE 3 1-O-(N-CBz-L-valyl-2-O-stearoylglycerol

a) Preparation of 1-O-(N-CBz-L-valyl)glycerol

CBz-L-valine (4.35 g, 17.3 mmol) was added to a fivefold excess ofglycerol (8 ml, 86.9 mmol) together with dicyclohexylcarbodiimide (4.29g 20.8 mmol) and 4-dimethylaminopyridine (0.212 g) at room temperature.After stirring overnight the suspension was filtered and DMF removed invacuo from the filtrate. The residue was redissolved in CH₂Cl₂, washedsuccessively with saturated NaHCO₃, brine, and water and then dried. Thecrude material was chromatographed on silica gel with 4/1 EtOAc-hexaneas eluent to yield 2.465 g. R_(f) (4/1 EtOAc-hexane) 0.17, (20/1CH₂Cl₂-methanol) 0.12.

b) Preparation of 1-O-(N-CBz-L-valyl)-3-O-pixylglyerol

The product of step a) (0.672 g, 20.1 mmol) was dissolved in drypyridine (3.5 ml) under nitrogen. 9-Chloro-9-phenylxanthene (pixylchloride, 0.65 g, 22.0 mmol, 1.1 eq—prepared as above) was added and themixture stirred at room temperature for 1.5 h. MeOH (1.5 ml) was addedand the mixture partitioned between 10 ml Et₂O and 10 ml saturatedNaHCO₃. The aqueous layer was extracted with more ether. The organiclayers were combined, dried and concentrated several times with tolueneto give a white solid. The crude material was chromatographed on silicagel with 3/1 hexane-EtOAc as eluent to give 0.681 g.

Alternatively a pixyl group can be put on by the procedure described byGaffney et al, Tetrahedron Lett 1997, 38, 2539-2542 using PxOH andacetic acid.

c) Preparation of 1-O-(N-CBz-L-valyl)-2-O-stearoyl-3-O-pixyl glycerol

Stearoyl chloride (496 ml, 1.3 eq) in 1.5 ml CH₂Cl₂ was added dropwiseto a solution of the product of step b) (0.658 g, 1.13 mmol) in 11 mlpyridine with stirring under N₂ in an ice bath. After 15 minutes themixture was stirred at room temperature overnight. The mixture wasdiluted with 20 ml Et₂O and washed with 10 ml saturated NaHCO₃. Theaqueous layer was extracted with more Et₂O. The organic layers werecombined, washed with brine (20 ml), dried over Na₂SO₄ and concentratedseveral times with toluene. The crude material (1.37 g) waschromatographed on 130 g silica gel with 6/1 hexane-EtOAc. An initialfraction of 500 ml was taken followed by 100 ml fractions. The desiredmaterial eluted in fractions 2-5 yielding 0.748 g.

d) Preparation of 1-O-(N-CBz-L-valyl)-2-O-stearoylglycerol

To a solution of the product of step c) (0.748 g, 872 mmol) dissolved in35 ml CH₂Cl₂ to make 0.025 M) was added pyrrole (16.5 mol eq) anddichloroacetic acid (5.5 mol eq) at room temperature. TLC after 5minutes showed complete reaction. The mixture was diluted with 300 mlCH₂Cl₂ and washed with 30 ml saturated NaHCO₃. The aqueous layer wasextracted with more CH₂Cl₂. The organic phases were combined, washedwith brine (30 ml), dried over Na₂SO₄ and concentrated. Crude materialwas chromatographed on silica gel with 2/1 hexane-EtOAc (with 0.3%acetic acid) as eluent to yield 0.363 g with R_(f) (2/1 hexane-EtOAc)0.21.

¹H NMR (CDCl₃) δ ppm 0.86-0.99 (m, 9H), 1.25 (s, 28H), 1.61 (m, 2H),2.16 (m, 1H), 2.32 (m, 2H), 3.74 (br s, 2H), 4.28-4.44 (m, 3H), 5.09 (m,1H), 5.11 (s, 2H), 5.22 (d, 1H), 7.36 (m, 5H)

EXAMPLE 4 1-O-stearoyl-3-O-(NCBz-L-valyl)glycerol

The product of Example 2, part a) (2.86 g, 7.99 mmol), DCC (0.9 g, 4.36mmol) 4-(N,N-dimethyl)aminopyridine (DMAP) (0.048 mg, 0.39 mmol) andN-CBz-L-valine (1 g, 3.98 mmol) were dissolved in CH₂Cl₂ (60 ml) and DMF(6 ml). The reaction was left at ambient temperature for 18 hours andthen filtrated. The solvent was evaporated under reduced pressure. Theresidue was dissolved in CH₂Cl₂ (100 ml) and filtrated. The crude titlecompound was purified by chromatography [SiO2, ether/hexane (1:2)] toyield 1.3 g of the desired product. Unreacted 1-stearoylglycerol may berecovered by eluting with CH₂Cl₂/MeOH (20:1).

¹H-NMR (CDCl₃): δ 5.25 (d, 1H), 5.11 (s, 2H), 4.30-4.05 (m, 6H), 2.65(d, 1H), 2.35 (t, 2H), 2.06 (m, 1H), 1.62 (m, 2H), 1.26 (s, 28H),1.00-0.84 (m, 9H).

EXAMPLE 5

To an ice cooled solution of 1-chloroethyl chloroformate (1.89 g, 13.2mmol) in dry CH₂Cl₂ (5 ml), was added the compound of Example 4 inCH₂Cl₂ (20 ml) followed by dry pyridine (1.2 ml, 29.6 mmol). Thereaction mixture was stirred with cooling under argon atmosphere untilTLC (ether/hexane, 1:2) indicated consumption of the starting material.After 1.5 h, the mixture was washed with water (3×5 ml), sat. NaHCO₃ (5ml) and dried (Na₂SO₄). Purification by chromatography [SiO₂(ether-hexane (1:2)] yielded the title compound (4.0 g).

¹H-NMR (CDCl₃): δ 7.36-7.32 (m, 5H), 6.40 (m, 1H), 5.24 (m, 1H), 5.11(s, 2H), 4.30 (m, 6H), 2.32 (m, 2H), 2.15 (m, 1H), 1.82 (m, 3H), 1.60(m, 2H), 1.25 (br s, 28H), 0.97 (m, 3H), 0.86 (m, 6H).

EXAMPLE 6

To a solution of the compound of Example 5 (3.4 g, 4,87 mmol) in dryacetonitrile (47 ml), was added sodium iodide (3.65 g, 24.3 mmol). Thesolution obtained was refluxed under argon atmosphere until NMRindicated consumption of the starting material. After 4.5 h, ether (50ml) was added and the mixture was filtrated. The solvent was removed byevaporation and the crude product dissolved in ether (50 ml). The ethersolution was washed with water (2×10 ml) and dried (Na₂SO₄) andevaporated under reduced pressure. Purification by chromatography [SiO₂,ether-hexane (1:2)] yielded the title compound (2.15 g).

¹H-NMR (CDCl₃): δ7.37 (m, 5H), 6.75 (m, 1H), 5.22 (m, 1H), 5.15 (s, 1H),4.3 (m, 6H), 2.32 (m, 1H), 2.22 (m, 2H), 1.6 (m, 2H), 1.25 (s, 28H),0.95 (m, 9H).

EXAMPLE 7

A solution of the compound of Example 3 (810 mg, 1.37 mmol) in 2.2 mLdry dichloromethane was cooled in an ice bath with stirring under argon.1-Chloroethyl chloroformate (298 μL, 2.74 mmol) was added, followed bythe dropwise addition of pyridine (665 μL, 8.22 mmol) in 2.5 mLdichloromethane. After 2.5 hr, the mixture was diluted with 25 mLdichloromethane and washed successively with 10 mL water and 10 mLbrine. The organic phase was dried over anhydrous sodium sulfate andconcentrated several times with toluene to give a yellow oil.Purification by flash column chromatography on silica gel with 40/1dichloromethane-diethyl ether gave the title compound as an oil (96 mg,quantitative yield).

¹H NMR (CDCl₃) δ ppm 0.85-0.98 (m, 9H), 1.25 (s, 28H), 1.60 (m, 2H),1.83 (d, 3H, J=5.8 Hz), 2.17 (m, 1H), 2.31 (t, 2H), 4.19-4.48 (m, 5H),5.11 (s, 2H), 5.22 (d, 1H), 5.27 (m, 1H), 6.38-6.43 (m, 1H), 7.36 (m,5H).

EXAMPLE 8

A solution of the compound of Example 7 (1.896 g, 2.71 mmol) and sodiumiodide (1.80 g, 12.0 mmol) in acetonitrile (27 mL) was refluxed at 80°C. under nitrogen. After 4.5 hours the reaction mixture was diluted with100 mL 1/1 hexane-diethyl ether and washed with 25 mL water. The aqueousphase was extracted with more solvent (25 mL). The organic phases werecombined, washed successively with 5% aqueous sodium thiosulfatesolution (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate,and concentrated in vacuo. Purification by flash column chromatographyon silica gel with 80/1 dichloromethane-methanol as eluant gave an oil(1.45 g) containing 90% of the title compound with 10% of the compoundof Example 7.

¹H NMR (CDCl₃) δ ppm 0.85-0.99 (m, 9H), 1.25 (s, 28H), 1.60 (m, 2H),2.17 (m 1H), 2.23 (d, 3H, J=6 Hz), 2.31 (t, 2H), 4.16-4.49 (m, 5H), 5.10(s, 2H), 5.20-5.29 (m, 2H), 6.69-6.79 (m, 1H), 7.36 (m, 5H).

EXAMPLE 9 4-Benzyloxy-2-(N-trityl-L-valyloxymethyl)-1-stearoyloxybutane

a) Synthesis of diethyl-2-(2-benzyloxyethyl)malonate

To a freshly prepared solution of sodium (0.95 g, 41.4 mmole) in 50 mlethanol was added a solution of diethylmalonate (6.4 g , 40 mmole) in 10ml ethanol and the mixture was stirred for 15 minutes. Then a solutionof 2-benzyloxy-1-iodoethane (11.5 g, 41,35 mmole) was added dropwise.The mixture was refluxed for four hours and than evaporated in vacuo.100 ml of water was added and the mixture was extracted three times with50 ml portions of diethylether. The organic phase was dried with sodiumsulfate and evaporated in vacuo and the product was isolated by silicagel column chromatography. Yield: 8.6 g

¹H-NMR (CDCl₃) 1.26 (m, 6H) 2.26 (m, 2H) 3.54 (m, 3H) 4.16 (m, 4H) 4.57(s, 2H) 7.32 (m, 5H)

b) Synthesis of 4-benzyloxy-2-hydroxymethyl-butanol-1.

To a stirred suspension of lithium aluminium hydride (3.0 g, 80 mmol) in100 ml diethylether was added dropwise a solution ofdiethyl-2-(2-benzyloxyethyl)malonate (8.5 g , 28.8 mmol) in 20 mldiethylether at about 15° C. The mixture was refluxed for two hours.About 4 ml water was dropwise added while cooling. The mixture wasfiltered and washed with dioxane. The filtrate was evaporated underreduced pressure and the product was isolated by silica gel columnchromatography.

Yield: 3.4 g ¹H-NMR (CDCl₃) 1.60 (m, 2H) 1.82 (m, 1H) 3.00 (m, 2H) 3.56(t, 2H) 3.69 (m, 4H) 4.50 (s, 2H) 7.32 (m, 5H)

c) Synthesis of 4-benzyloxy-2-(N-trityl-L-valyloxymethyl)-butanol-1

To a solution of N-trityl-L-valine (4.66 g, 13 mmol) and4-benzyloxy-2-hydroxymethyl-butanol-1 (3.3 g, 15.6 mmole) in 50 mldichloromethane was added DCC (3.0 g, 14.5 mmole) and DMAP (0.18 g, 1.45mmole) and the mixture was stirred for three days. The mixture wascooled to 5° C. and the urethane was filtered. The solution wasevaporated under reduced pressure and the product was isolated by silicagel column chromatography.

Yield: 2.5 g ¹H-NMR (CDCl₃) 1.00 (m, 6H) 1.55 (m, 4H) 1.72 (m, 1H) 2.18(m, 1H) 2.70 (m, 1H) 3.27 (m, 2H) 3.43 (m, 3H) 4.50 (s, 2H) 7.26 (m,20H)

d) Synthesis of4-benzyloxy-2-(N-trityl-L-valyloxymethyl)-1-stearoyloxybutane.

To a solution of 4-benzyloxy-2-(N-trityl-1-valyloxymethyl)-butanol-1(2,4 g, 4.35 mmol) in 50 ml dichloromethane was added pyridine (1.72 g,21.7 mmol). The solution was cooled to 10° C. and a solution of stearoylchloride (2.64 g, 8.7 mmol) in 10 ml dichloromethane was added dropwisebetween 10° C. and 15° C. The mixture was stirred overnight at roomtemperature. 100 ml of 5% sodium hydrogen carbonate solution was addedand the mixture stirred for 30 minutes. The organic phase was seperatedand the water phase was extracted two times with dichloromethane. Thecombined organic phases were dried with sodium sulfate and concentratedin vacuo. The product was isolated by silica gel column chromatography.

Yield: 3.0 g ¹H-NMR (CDCl₃) 0.98 (m, 9H) 1.26 (m, 28H) 1.54 (m, 2H) 1.94(m, 1H) 2.25 (m, 2H) 3.23 (m, 2H) 3.44 (m, 2H) 3.58 (m, 1H) 3.91 (m, 2H)4.10 (m, 1H) 4.47 (s, 2H) 7.28 (m, 20H)

EXAMPLE 10 5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoic acid

a) Preparation of 2-allyl 1,3-propanediol

Diethyl allylmalonate (20 ml, 101 mmol) in anhydrous ether (100 ml) wasadded dropwise to a stirred solution of lithium aluminium hydride (9.6g, 253 mmol) at 0° C. The reaction was warmed up to room temperature andkept for 5 hours. It was cooled down to 0° C. and water (12 ml) wascarefully added dropwise. After stirring for 30 min, the mixture wasfiltered through Celite and then washed with ethanol (2×500 ml). Thesolution was dried under vacuum giving 9.5 g product

¹H-NMR (CDCl₃): 5.78 m, 1H), 5.03 (m, 2H), 3.78 (m, 2H), 3.69 (m, 2H),2.06 (t, 2H), 1.87 (m, 1H).

b) Preparation of 1-O-(N-trityl-L-valyl)-2-allyl-1,3-propandiol

To a solution of N-trityl-L-valine (5.5 g, 15.2 mmole),2-allyl-1,3-propandiol (4.4 g, 38 mmol), N,N-dimethylamino pyridine (183mg, 1.5 mmol) in dichloromethane (120 ml) was added DCC (3.5 g, 16.7mmol). The reaction was kept under reflux overnight. After filtrationthrough Celite, the organic phase was washed with sodium hydrogencarbonate aqueous solution and dried. Silica gel column chromatographygave 4.6 g intermediate 1-O-(N-trityl-L-valyl)-2-allyl-1,3-propandiol.

c) Preparation of1-O-(N-trityl-L-valyl)-2-allyl-3-stearoyl-1,3-propandiol.

To a solution of 1-O-(N-trityl-L-valyl)-2-allyl-1,3-propandiol (1.83 g,4 mmol) in dichloromethane (40 ml) and pyridine (3.2 ml, 40 mmol) at 0°C. was added dropwise stearoyl chloride (3.62 g, 12 mmol) indichloromethane. The solution was warmed up to room temperature, andkept for 3 hr. It was then washed with sodium hydrogen carbonate aqueoussolution and dried. The product was isolated by silica gel columnchromatography. 1.9 g

¹H-NMR (CDCl₃): 7.30 (m, 15 H), 5.70 (m, 1H), 4.99 (m, 2H), 3.93 (m,2H), 3.55 (m, 1H), 3.27 (m, 2H), 2.68 (m, 1H), 2.30 (m, 2H), 2.23 (m,1H), 2.01 (m, 2H), 1.85 (m, 1H), 1.62 (m, 2H), 1.3 (m, 28H), 0.98 (dd,6H), 0.91 (t, 3H).

d) Preparation of3-(N-trityl-L-valyloxymethyl)-4-stearoyloxy-butyraldehyde

1-O-(N-trityl-L-valyl)-2-allyl-3-stearoyl-1,3-propandiol (580 mg, 0.8mmol) was dissolved in dioxane (5 ml). To the solution were added osmiumtetraoxide (20 mg, 0.08 mmole) and pyridine (0.05 ml, 0.64 mmole). Asolution of sodium periodate in water (3.5 ml) was added to the reactionmixture. The reaction was kept overnight and then cooled down to 0° C.An aqueous solution of sodium hydrogen sulfite was added and the mixturewas extracted with dichloromethane. The organic phase was dried andpurified by silica gel column chromatography. Yield. 250 mg

¹H-NMR (CDCl₃): 9.68 (s, 1H), 7.25 (m, 15 H), 3.92 (m, 2H), 3.58 (m,1H), 2.32 (m, 2H), 2.68 (m, 1H), 2.34 (m, 7 H), 1.58 (m, 2H), 1.53 (m,28 H), 0.96 (dd, 6H), 0.86 (t, 3H).

f) Preparation of benzyl3-(N-trityl-L-valyloxymethyl)-4-stearoyloxyhexen-2-oate

To the solution of3-(N-trityl-L-valyloxymethyl)-4-stearoyloxy-butyraldehyde (15.8 g, 21.8mmole) in cichloromethanewere added (benzyloxycarbonylmethyl)triphenylphosphonium bromide (10.7 g, 21.8 mmole) and triethylamine(2.21 g, 21.8 mmole). The reaction was kept overnight at roomtemperature, and the mixture was evaporated. To the residue was addeddiethyl ether (200 ml and kept at 4° C. for two hours. It was thenfiltered and the filtrate was evaporated and the product was purified bysilica gel column chromatography. Yield. 10 g

¹H-NMR (CDCl₃): 7.30 (m, 20 H), 6.89 (m, 1H), 5.88 (d, 1H), 5.19 (d,2H), 3.95 (m, 2H), 3.57 (m, 1H), 3.29 (, 2H), 2.68 (m, 1H), 2.23 (m,5H), 1.93 (m, 1H), 1.60 (m, 2H), 1.32 (m, 28 H), 0.95 (dd, 6H), 0.89 (t,3 H).

g) Preparation of 3-(N-trityl-L-valyloxymethyl)4-stearoyloxyhexanoate

To a solution of benzyl3-(N-trityl-L-valyloxymethyl)-4-stearoyloxyhexen-2-oate (70 mg, 0.08mmole) in methanaol (3 ml) and ethyl acetate (1 ml) was added sodiumhydrogen carbonate (10 mg) and palladium black (20 mg). The reaction waskept under hydrogen at atmospheric pressure for 2 hr. The mixture wasfiltered and evaporated. The residue was dissolved in dichloromethaneand washed successively with aqueous EDTA solution and cold aqueous 2%citric solution. The organic phase was evaporated to give 61 mg product

¹H-NMR (CDCl₃): 7.30 (m, 15 H), 3.93 (m, 2H), 3.57 (m, 1H), 3.25 (m,2H), 2.30 (dt, 4H), 2.20 (m, 1H), 1.70 (m, 1H), 1.62 (m, 4H), 1.30 (m,28 H), 0.95 (dd, 6 H), 0.87 (t, 3 H).

EXAMPLE 11 3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4stearoyloxy-butyricacid

a) Preparation of1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-1,3-propandiol

To a solution of 2-allyl-1,3-propandiol (4.6 g, 40 mmole) andN-benzyloxycarbonyl valine (5.02 g, 20 mmole) in dichloromethane wasadded dimethylaminopyridine (244 mg, 2 mmol), and DCC (4.5 g, 22 mmol).After two hours, the mixture was filtered through Celite, evaporated andthe product, 1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-1,3-propandiol,isolated to yield 5.01 g.

¹H-NMR (CDCl₃): 7.36 (m, 5H), 5.78 (m, 1H), 5.26 (d, 1H), 5.11 (s, 2H),5.06 (d, 2H), 4.22 (m, 3H), 3.59 (m, 2H), 2.13 (m, 3H), 1.98 (m, 2H),0.94 (dd, 6 H).

b) Preparation of1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-3-O-stearoyl-1,3-propandiol.

To a solution of1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-1,3-propandiol (4.46 g, 12.7mmol) in dichloromethane (70 ml) and pyridine (6.1 ml, 76 mmole) in icebath was added stearoyl chloride (7.8 g, 26 mmole). The reaction mixturewas warmed up to room temperature and kept for one hour. It was thenpoured into aqueous sodium hydrogen carbonate solution, the organicphase was dried and the product1-O-benzyloxycarbonyl-L-valyl)-2-allylyl-3-O-stearoyl-1,3-propandiol waspurified by silica gel column chromatography. 6.7 g

¹H-NMR (CDCl₃): 7.34 (m, 5H), 5.77 (m, 1H), 5.30 (d, 1H), 5.11 (s, 2H),5.08 (d, 2H), 4.32 (m, 1H), 4.10 (m, 4 H), 2.29 (m, 2H), 2.13 (m, 4H),1.62 (m, 3 H), 1.25 (m, 28H), 0.90 (m, 9 H).

c) Preparation of3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butyric acid.

Potassium permanganate (756 mg, 4.8 mmole) was dissolved in water (7.5ml). The solution was kept under strong stirring for 10 min. A solutionof1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-3-O-stearoyl-1,3-propandiol(1 g, 1.6 mmol) and tetrabutylammonium bromide (77 mg, 0.24 mmole) inbenzene (5 ml) was added. The slurry was stirred for 1.5 hr, anddichloromethane was added. A sodium bisulfite aqueous solution was addedto the slurry until the mixture discolored. The organic phase wasacidified with acetic acid and washed with water. After evaporation, theproduct 3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butyricacid (390 mg) was isolated by silica gel column chromatography.

¹H-NMR (CDCl₃): 7.33 (m, 5H), 5.38 (d, 1H), 5.11 (s, 2H), 4.14 (m, 5 H);2.60 (m, 1H), 2.45 (m, 2 H), 2.29 (t, 2 H), 2.18 (m, 1 H), 1.58 (m, 2H), 1.25 (m, 28 H), 0.90 (m, 9 H).

EXAMPLE 122′,3′-dideoxy-3′-fluoro-5′-O-[5-(L-valyloxymethyl)-6-stearoyloxyhexanoyl]guanosine

a) Preparation of2′,3′-dideoxy-3′-fluoro-5′-O-[5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoyl]guanosine

To a solution of 5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoicacid (462 mg, 0.6 mmole) and 2′,3′-dideoxy-3′-fluoroguanosine (340 mg,1.25 mmol) in DMF (3 ml) were added dimethylaminopyridine (7 mg, 0.06mmole), and DCC (136 mg, 0.66 mmol). The reaction was kept at roomtemperature overnight, and then at 40° C. for two hours. The reactionmixture was filtered through Celite and poured into dichloromethane, andwashed with aqueous sodium hydrogen carbonate solution. The product2′,3′-dideoxy-3′-fluoro-5′-O-[5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoyl]guanosinewas isolated by silica gel column chromatography. (93 mg)

¹H-NMR (DMSO δ-6): 7.88 (s, 1H), 7.29 (m, 15 H), 6.52 (s, 2H), 6.17 (dd,1H) 5.45 (m, 1H), 4.35 (m, 1H), 4.20 (m, 2 H), 3.82 (m, 2H), 3.50-2.60(m, 5 H), 2.30 (m, 4 H), 2.10 (m, 1 H), 1.70 (m, 1H), 1.50 (m, 4 H),1.22 (m, 28 H), 0.85 (m, 9 H).

b) Preparation of2′,3′-dideoxy-3′-fluoro-5′-O-[5-(L-valyloxymethyl)-6-stearoyloxyhexanoyl]guanosine

The compound of step b) (90 mg, 0.088 mmole) was N-deprotected bytreatment with 80% acetic acid (5 ml) at room temperature for 30 min. Itwas evaporated and product was purified by silica gel columnchromatography to yield 72 mg of the title compound.

¹H-NMR (DMSO δ-6): 7.88 (s, 1H), 6.54 (s, 2H), 6.18 (dd, 1H), 5.48 (dd,1H), 4.27 (dt, 1 H), 4.19 (m, 2 H), 3.98 (m, 4H), 3.17-2.55 (m, 4 H),2.29 (m, 4 H), 1.95 (m, 1 H), 1.75 (m, 1 H), 1.50 (m, 4H), 1.21 (m, 28H), 0.84 (m, 9 H).

EXAMPLE 132′,3′-Dideoxy-3′-fluoro-5′-O-[3-(L-valyloxymethyl)-4-stearoyloxy-butanoyl]guanosine

a) Preparation of2′,3′-dideoxy-3′-fluoro-5′-O-[3-(N-benzyloxycarbonyl-L-valyloxy)-4-stearoyloxy-butanoyl]guanosine

To a solution of 2′,3′-dideoxy-3′-fluoroguanosine (113 mg, 0.42 mmol)and 3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butyric acid(140 mg, 0.21 mmol) in DMF (2 ml) were added dimethylaminopyridine (3mg, 0.02 mmol) and DCC (52 mg, 0.25 mmol). After two days,dichloromethane (10 ml) and a few drops of acetic acid were added andthe organic phase was filtered through Celite. The filtrate was washedwith aqueous sodium hydrogen carbonate solution and the product2′,3′-dideoxy-3′-fluoro-5′-O-[3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butanoyl]guanosinewas isolated by silica gel column chromatography to yield 51 mg.

¹H-NMR (CDCl₃): 7.79 (d, 1H), 7.26 (m, 5 H), 6.38 (s, 2H), 6.23 (t, 1H),5.44 (m, 2H), 5.08 (s, 2H), 4.50-4.10 (m, 8H), 3.15-2.40 (m, 5 H), 2.30(t, 2 H), 2.14 (m, 1H), 1.58 (m, 2H), 1.24 (m, 28H), 0.87 (m, 9 H).

b) Preparation of2′,3′-Dideoxy-3′-fluoro-5′-O-[3-(L-valyloxymethyl)-4-stearoyloxy-butanoyl]guanosine

The product of step a) (76 mg, 0.084 mmole) was dissolved in a mixedsolvent of methanol (3 ml), ethyl acetate (0.5 ml) and acetic acid (0.01ml). To the solution was added palladium black (10 mg). After 2 hr,additional 10 mg palladium black was added. After 3 hr, the mixture wasfiltered and evaporated. The residue was dissolved in dichloromethaneand washed with aqueous EDTA solution. The organic phase was dried andcoevaporated with toluene giving the title compound as the acetate salt.Yield 65 mg.

¹H-NMR (DMSO δ-6+D₂O): 7.87 (s, 1H), 5.16 (dd, 1H), 5.37 (dd, 1H), 4.24(m, 3H), 4.01 (m, 4H), 3.10-2.60 (m, 3H), 2.40 (m, 2H), 2.24 (t, 2 H),1.70 (m, 1H), 1.48 (m, 2H), 1.25 (m, 28H), 0.82 (m, 9H).

EXAMPLE 14 3-[1-(N-CBz-L-valyl)-2-stearoyl]propyl chloroformate

1-(N-CBz-L-valyl)-2-stearoyl) glycerol (300 mg, 0.5 mmole) was dissolvedin 20% phosgene in toluene (15 ml ). After 18 h, the solution wasevaporated and the residue was coevaporated with toluene for severaltime, giving title product in quantitative yield. This product forms acarbonate with the target nucleoside using standard methodology, forinstance reacting in a 10:1 DMF/pyridine solution at 0° C. for 3 to 24hours, pouring into NaHCO₃ solution and extraction with dichloromethane.The amino acid is deprotected, for instance with palladium black in amethanol, ethyl acetate, acetic acid solution to yield thenucleoside-O-[1-(L-valyl)-2-stearoyl-3-propyloxy carbonyl]

¹H-NMR (CDCl₃): 7.40 (m, 5H), 5.28 (m, 2H), 5.10 (s, 2H), 4.35 (m, 5H,2.35 (m, 2H), 2.17 (m, 1 H), 1.56 (m, 2H), 1.30 (m, 28 H), 0.95 (m, 9H).

EXAMPLE 15 5-(N-FMOC-L-valyloxy)-4-stearoyloxy-pentanoic acid

a) Benzyl 4,5-dihydroxy-2-pentenoate.

A mixture of DL-glycerinaldehyde (4.5 g, 50 mmole) and(benzyloxycarbonylmethyl)-triphenyl-phosphoniumbromide (24.57 g, 50mmole) in 100 ml 1,2-epoxybutane was refluxed overnight. The mixture wasevaporated under vacuum and the product was isolated by silica gelcolumn chromatography.

Yield: 8 g=71% ¹H-NMR (CDCl₃) 2.50 (s, 1H) 2.96 (s, 1H) 3.54 (m, 1H)3.70 (m, 1H) 4.38 (m, 1H) 5.12 (s, 2H) 6.14 (m, 1H) 6.90 (m, 1H) 7.30(m, 5H)

b) Benzyl 5-(N-FMOC-L-valyloxy)-4-hydroxy-2-pentenoate.

A mixture of benzyl 4,5-dihydroxy-2-pentenoate (4.4 g, 20 mmole),N-FMOC-L-valine (5.8 g, 17 mmole) and DMAP (0.21 g, 1.7 mmole) in 100 mldichloromethane was cooled to about 10° C. A solution of DCC (4.2 g, 20mmole) in 25 ml dichloromethane was added dropwise at the sametemperature and the mixture was stirred overnight at room temperature.The mixture was cooled to 5° C. and the urethane was filtered. Thefiltrate was evaporated under reduced pressure and the product wasisolated by silica gel column chromatography.

Yield: 6.6 g=71% ¹H-NMR (CDCl₃) 0.91 (m, 6H) 2.12 (m, 1H) 4.38 (m, 5H)5.14 (s, 2H) 5.24 (m, 1H) 6.20 (m, 1H) 6.92 (m, 1H) 7.30 (m, 13H)

c) Benzyl-5-(N-FMOC-L-valyloxy)-4-stearoyloxy-2-pentenoate

To a solution of benzyl-5-(N-FMOC-L-valyloxy)-4-hydroxy-2-pentenoate(6.5 g, 12 mmol) and pyridine (2.0 g, 25 mmole) in 100 mldichloromethane at 10° C. was added dropwise a solution ofstearoylchloride (4.55 g, 15 mmol) in 25 ml dichloromethane. The mixturewas stirred overnight. 100 ml of 5% sodium hydrogencarbonate solutionwas added and the mixture was stirred for 30 minutes. The organic phasewas seperated and the water phase was extracted two times withdichloromethane. The combined organic phases were dried with sodiumsulfate and concentrated in vacuo. The product was isolated by silicagel column chromatography Yield: 7.8 g=80%

¹H-NMR (CDCl₃) 0.88 (m, 9H) 1.25 (m, 28H) 1.58 (m, 2H) 2.14 (m, 1H) 2.32(m, 2H) 4.22 (m, 5H) 5.19 (s, 2H) 5.25 (m, 1H) 6.12 (m, 1H) 6.85 (m, 1H)7.35 (m, 13H).

d) 5-(N-FMOC-L-valyloxy)-4-stearoyloxy-pentanoic acid.

A solution of benzyl 5-(N-FMOC-L-valyloxy)-4-stearoyloxy-2-pentenoate(3.8 g, 4.69 mmole) in 50 ml ethyl acetate was hydrogenated with 10%palladium on charcoal (0.5 g) at normal pressure for five hours at roomtemperature. The catalyst was filtered and washed with ethyl acetate and1,4-dioxane. The solution was evaporated under reduced pressure Yield:3.3 g=99%

¹H-NMR (CDCl₃) 0.92 (m, 9H) 1.25 (m, 28H) 1.54 (m, 2H) 1.98 (m, 2H) 2.18(m, 1H) 2.28 (m, 2H) 2.41 (m, 2H) 4,32 (m, 5H) 5.13 (m, 1H) 5.33 (m, 1H)7.50 (m, 8H)

EXAMPLE 16 3-(N-FMOC-L-valyloxy)-2-stearoyloxypropionic acid

a) Benzyl 2,3-dihydroxypropionate.

A mixture of D,L-glyceric acid, calcium salt dihydrate (2.9 g, 10 mmole)and benzylbromide (3.8 g, 22 mmole) in 25 ml DMF was stirred at 60° C.overnight. The mixture was evaporated under reduced pressure and theproduct was isolated by silica gel chromatography. Yield: 4 g=100%

¹H-NMR (CDCl₃) 3.26 (s, 1H) 3.90 (m, 2H) 4.32 (m, 1H) 5.25 (s, 2H) 7.29(m, 5H)

b) Benzyl 3-(N-FMOC-L-valyloxy)-2-hydroxypropionate

A solution of benzyl-2,3-dihydroxypropionate (4.0 g , 20 mmole )N-FMOC-L-valine (5.4 g, 16 mmole) and DMAP (0.2 g, 1.6 mmole) in 80 mldichloromethane was cooled to about 10° C. A solution of DCC (4.12 g, 20mmole) in 25 ml was added dropwise at the same temperature and themixture was stirred overnight at room temperature. The mixture wascooled to 5° C. and the urethane was filtered.

The solution was evaporated under reduced pressure and the product wasisolated by silica gel chromatography. Yield: 4.7 g=45%

¹H-NMR (CDCl₃) 0.88 (m, 6H) 2.05 (m, 1H) 4.40 (m, 6H) 5.23 (m, 3H) 7.50(m, 13H)

c) Benzyl 3-(N-FMOC-L-valyloxy)-2-stearoyloxypropionate

To a stirred solution of benzyl3-(N-FMOC-L-valyloxy)-2-hydroxypropionate (4.6 g 8.89 mmole) andpyridine (1.41 g, 17.8 mmole) in 80 ml dichloromethane was addeddropwise a solution of stearoylchloride (3.64 g, 12 mmole) in 20 mldichloromethane and the mixture was stirred overnight at roomtemperature. 100 ml of 5% sodium hydrogencarbonate solution was addedand the mixture stirred for 30 minutes. The organic phase was seperatedand the water phase was extracted two times with dichloromethane. Thecombined organic phases were dried with sodium sulfate and concentratedin vacuo. The product was isolated by silica gel chromatography. Yield:6.1 g=87%

¹H-NMR (CDCl₃) 0.88 (m, 9H) 1.26 (m, 28H) 1.56 (m, 2H) 2.06 (m, 1H) 2.34(m, 2H) 4.36 (m, 6H) 5.19 (s, 2H) 5.32 (m, 1H) 7.50 (m, 13H)

d) 3-(N-FMOC-L-valyloxy )-2-stearoyloxypropionic acid.

A solution of benzyl 3-(N-FMOC-L-valyloxy)-2-stearoyloxypropionate (0.78g, 1 mmole) in 20 ml ethyl acetate was hydrogenated with 10% palladiumon charcoal (0.2 g) at normal pressure for three hours at roomtemperature. The catalyst was filtered and washed with ethyl acetate and1,4-dioxane. The solution was evaporated under reduced pressure. Yield:0.63 g=90%

¹H-NMR (CDCl₃) 0.88 (m, 9H) 1.24 (m, 28H) 1.40 (m, 2H) 2.12 (m, 3H) 4.30(m, 5H) 5.16 (m, 1H) 5.60 (m, 1H) 7.40 (m, 8H)

EXAMPLE 171-(N-Benzyloxycarbonyl-L-valyloxymethyl)-2-stearoyloxyethoxycarbonylchloride

Bis(trichloromethyl) carbonate (160 mg; 0.54 mmol) was added withstirring to a solution of1-(N-benzyloxycarbonyl-L-valyl)-3-stearoylglycerol;1-(N-benzyloxycarbonyl-L-valyloxy)-3-stearoyloxy-2-propanol; preparativeexample 4; (660 mg; 1.12 mmol) and triethylamine (200 mg; 2.0 mmol) indichloromethane (5 ml) at room temperature. After 1 h, n-hexane (10 ml)was added and the precipitated triethylamine hydrochloride was filteredoff through a short column of silica gel, the product eluted with afurther amount of n-hexane, and the solvent evaporated in vacuum toyield 650 mg (89%) of the title compound.

¹³C NMR (CDCl₃, 62.975 MHz): δ 172.8 (stear-COO); 171.2 (Val-COO); 155.9(CONH); 154.1 (COCl); 136.0 (Ph-Cl-Val); 128.1-127.7 (Ph); 67.2 (CHOH);66.7 (Ph CH₂); 63.1 (ValCOOCH₂); 61.8 (stear-COOCH₂): 58.7 (Val-αC);33.7 (stear-C2); 31.6 (stear-C16); 31.0 (Val-βC); 29.3-28.8(stear-C4-15); 24.5 (stear-C3); 18.6 and 17.1 (Val 2 CH₃); 13.8(stear-C18).

EXAMPLE 18 3-(N-CBz-L-valyloxymethyl)-4-stearoyloxybutylchloroformate

a) 3-(N-CBz-L-valyloxymethyl)-4-stearoyloxy-butanol.

To a stirred solution of4-stearoyloxy-3-(N-CBz-L-valyloxymethylbutyraldehyde (preparedanalogously to preparative example 6. step d) using CBz protectedvaline) (2.0 g, 3.2 mmole) in 25 ml methanol at 10° C. was added sodiumborohydride (0.6 g, 16 mmole) in small portions. The mixture was stirredfor 30 minutes and then acidified with acetic acid. The mixture wasdiluted with water and extracted three times with dichloromethane. Theorganic phase was dried with sodium sulfate and concentrated in vacuo.The product was isolated by silica gel column chromatography. Yield: 1.5g=75%.

¹H-NMR (CDCl₃) 0.88 (m, 9H) 1.25 (m, 28H) 1.52 (m, 4H) 2.24 (m, 3H) 3.68(m, 2H) 4.12 (m, 4H) 4.24 (m, 1H) 5.08 (s, 2H) 5.22 (m, 1H) 7.36 (m, 5H)

b) 3-(N-CBz-L-valyloxymethyl)-4-stearoyloxybutyl chloroformate

A solution of the intermediate of step a) in 20 ml of a 20% solution ofphosgene in toluene was stirred overnight. The mixture was evaporatedunder reduced pressure to yield the title compound. Yield 1.5 g=97%.

¹H-NMR (CDCl₃) 0.88 (m, 9H) 1.28 (m, 28H) 1.58 (m, 2H) 1.72 (m, 2H) 2.15(m, 1H) 2.31 (m, 2H ) 4.08-4.42 (m, 5H) 5.10 (s, 2H) 5.22 (m, 1H) 7.36(m, 5H)

EXAMPLE 192′,3′-dideoxy-3′-fluoro-5′-O-[1-(L-valyloxy)-2-stearoyloxy-3-propyloxycarbonyl]guanosine

a) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-[1-(N-CBz-L-valyloxy)-2-stearoyloxy-3-propyloxycarbonyl]guanosine.

To a solution of 2′,3′-dideoxy-3′-fluoro-guanosine (270 mg, 1 mmole) inDMF (10 ml) and pyridine (1 ml) was added3-{1-(N-CBz-L-valyl)-2-stearoyl}propyl chloroformate (619 mg, 0.5 mmole)at 0° C. After 3 h, the reaction mixture was poured into sodium hydrogencarbonate solution and extracted with dichlorometane.

The organic phase was dried in vacuo, and2′,3′-dideoxy-3′-fluoro-5′-O-[1-(N-CBz-L-valyloxy)-2-stearoyloxy-3-propyloxycarbonyl]guanosine was isolated by silica gel column chromatography (195mg).

¹H-NMR (CDCl₃): 7.69 (s, 1H), 7.31 (m, 5H), 6.50 (m, 2H), 6.32 (m, 1H),5.3 (m, 2H), 5.09 (m, 2H), 4.35 (m, 7H), 2.60 (m, 2H), 2.31 (t, 2H),2.20 (m, 1H), 1.58 (m, 2H), 1.23 (m, 28 H), 0.92 (m, 9H).

b) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-[1-(L-valyloxy)-2-stearoyloxy-3-propyloxycarbonyl]guanosine.

2′,3′-dideoxy-3′-fluoro-5′-O-[1-(N-CBz-L-valyloxy)-2-stearoyloxy-3-propyloxycarbonyl]guanosine (190 mg), was dissolved in a mixed solvent ofmethanol (6 ml), ethyl acetate (2 ml) and acetic acid (1 ml). To thesolution was added palladium black (30 mg), and the reaction mixture waskept under hydrogen for 2 h. It was then filtered and the filtrate wasevaporated and the titled product was isolated by silica gel column. 110mg.

¹H-NMR (DMSO-δ6): 7.86 (ds, 1H), 6.51 (s, 2H), 6.17 (dd, 1H), 5.48 (m,1H), 5.20 (m, 1H), 4.25 (m, 7H), 2.70 (m, 2) 2.27 (m, 2H), 1.72 (m, 1H),1.47 (m, 2H), 1.22 (m, 28 H), 0.84 (m, 9H).

EXAMPLE 202′,3′-dideoxy-3′-fluoro-5′-O-[5-(L-valyloxy)-4-stearoyloxy-pentanoyl]guanosine

To a solution of 2′,3′-dideoxy-3′-fluoroguanosine (0.27 g, 1 mmole) and5-(N-FMOC-L-valyloxy)-4-stearoyloxypentanoic acid (0.94 g, 1.3 mmole) in30 ml DMF was added DMAP (16 mg, 0.13 mmol) HOBT (0.176 g, 1.3 mmole )and DCC (0.248 g, 1.2 mmole). The mixture was stirred for three days atroom temperature. 4 g silica gel were added and the mixture evaporate invacuo, The product,2′,3′-dideoxy-3′-fluoro-5′-O-[5-(FMOC-L-valyloxy)-4-stearoyloxy-pentanoyl]guanosinewas separated by silica gel chromatography. Yield 0.45 g

¹H-NMR (DMSOδ-6) 0.88 (m, 9H) 1.20 (m, 28H) 1.45 (m, 2H) 1.78 (m, 2H)2.18 (m, 2H) 2.36 (m, 1H) 2.62 (m, 2H) 3.88 (m, 1H) 4.22 (m, 6H) 4.92(m, 1H) 5.45(m, 1H) 6.19 (m, 1H) 6.52 (s, 2H) 7.26-7.88 (m, 8H)

The protected intermediate is deprotected as shown above to yield thetitle compound.

EXAMPLE 202′,3′-dideoxy-3′-fluoro-3′-O-[3-(N-FMOC-L-valyloxy)-2-stearoyloxypropanoyl]guanosine

To a stirred mixture of 3-(N-FMOC-L-valyloxy)-2-stearoyloxyproparoicacid (0.61 g, 0.88 mmol) in 5 ml dry diethlether was added one drop DMFand thionyl chloride (0.52 g, 4.4 mmole). The mixture was refluxed fortwo hours and then evaporated under reduced pressure. The product wasdissolved in dry dichloromethane and added dropwise to a solution of2′,3′-dideoxy-3′-fluoroguanisine (0.215 g, 0.8 mmole) and pyridine (0.35g, 4.4 mmole) in 20 ml DMF. The solution was stirred overnight. Twogrammes of silica gel were added and the mixture was evaporated invacuo. The product was isolated by silica gel chromatography. Yield:0.19 g=25%

¹H-NMR (CDCl₃) 0.88 (m, 9H) 1.25 (m, 28H) 1.62 (m, 2H) 2.12(m, 1H) 2.38(m, 2H) 2.58 (m, 2H) 4.12-4.76 (m, 6H) 5.32 (m, 2H) 6.12 (m, 1H) 6.26(m, 1H) 6.44 (m, 1H) 7.12-7.78 (m, 8H).

EXAMPLE 21 1-(N-CBz-L-valyl)-3-stearoyl-2-propyl succinate monoester

1-(N-CBz-L-valyl)-3-stearoyl-glycerol (886 mg, 1.5 mmole) and succinicanhydride (450 mg, 4.5 mmole) were dissolved in a mixed solvent of DMF(15 ml) and pyridine (1 ml). The reaction was kept at room temperaturefor 3 h, and then at 60° C. for 5 h. The reaction mixture was pouredinto a solution of acetic acid and water and extracted withdichloromethane. The organic phase was washed with water and evaporated,and the product was isolated by silica gel column chromatography toyield 900 mg.

¹H-NMR (CDCl₃): 7.43 (m, 5H), 5.27 (m, 1H), 5.09 (m, 2H), 4.21 (m, 5H),2.54 (m, 4H), 2.29 (t, 2H), 2.13 (m, 1H), 1.59 (m, 2H), 1.25 (m, 28 H),0.90 (m, 9H).

EXAMPLE 222′,3′-dideoxy-3′-fluoro-5′-O-{3-[1-(L-valyloxy)-3-stearoyloxy-2-propyloxycarbonyl]-propanoyl}guanosine

To a solution of 2′,3′-dideoxy-3′-fluoro-guanosine (351 mg, 1.3 mmole)and 1-(N-CBz-L-valyl)-3-stearoyl-2-propyl succinate monoester (900 mg,1.3 mmole) in DMF (15 ml) were added dimethylaminopyridine (24 mg, 0.2mmole), 1-hydroxybenzothiazole (175 mg, 1.3 mmole), DCC (321 mg, 1.56mmole). After 48 h, the reaction mixture was filtered. The filtrate waspoured into sodium hydrogen carbonate solution and extracted withdichloromethane. The product2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1-(N-CBz-L-valyl)-3-stearoylglyceroloxy carbonyl]propanoyl}guanosine was isolated by silica gelcolumn chromatography. 780 mg

¹H-NMR (DMSO-d6): 7.89 (s, 1H), 7.34 (m, 5H), 6.50 (s, 2H), 6.17 (dd,1H), 5.46 (m, 1H), 5.38 (m, 1H), 5.02 (s, 2H), 4.22 (m, 7H), 3.32 (s,4H), 2.80 (m, 2H), 2.57 (m, 2H), 2.31 (t, 2H), 2.05 (m, 1H), 1.48 (m,2H), 1.21 (m, 28 H), 0.84 (m, 9H).

To the solution of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1-(N-CBz-L-valyl)-3-stearoyl-2-propyloxycarbonyl]propanoyl}guanosine (460 mg, 0.5 mmole) in a mixed solvent ofmethanol (10 ml), ethyl acetate (3 ml) and acetic acid (2 ml) was addedpalladium black (50 mg). After reaction under hydrogen atmosphere for 2h, the mixture was filtered and the filtrate was dried. The titledproduct was isolated by silica gel column chromatography. 360 mg.

¹H-NMR (DMSO-d6): 7.89 (s, 1H), 6.51 (s, 2H), 6.16 (dd, 1H), 5.48 (m,1H), 5.17 (m, 1H), 4.28 (m, 7H), 2.90 (m, 2H), 2.58 (m, 4H), 2.28 (t,2H), 1.85 (m, 1H), 1.49 (m, 2H), 1.22 (m, 28 H), 0.85 (m, 9H).

EXAMPLE 23

A solution of stearoyl chloride (12.1 g, 40 mmol, 1.0 eq) in CH₂Cl₂ (100ml) was slowly (1 h) added to a solution of2,2-bis(hydroxymethyl)propionic acid (26.8 g, 200 mmol, 5.0 eq) inpyridine (400 ml) at room temperature. The reaction mixture was stirredat room temperature overnight and thereafter concentrated (100 ml) undervacuum. The reaction mixture was slowly treated with saturated NaHCO₃(400 ml) and thereafter extracted with CH₂Cl₂ (3×300 ml). The organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated in vacuum. The crude material was chromatographed on silicagel (500 g) with 19/1 to 4/1 CH₂Cl₂-MeOH as eluent, to yield themonostearoyl ester, R_(f) (9/1 CH₂Cl₂-MeOH) 0.33. 12.5 g (78%).

A solution of N-Cbz-L-valine (18.85 g, 75 mmol, 2.4 eq) and DMAP (855mg, 7 mmol, 0.22 eq) in CH₂Cl₂ (800 ml) was cooled to 0° C. and treatedwith DCC (14.4 g, 70 mmol, 2.2 eq). The reaction mixture was stirred atroom temperature for 30 min and thereafter slowly (1 h) treated with asolution of the above monostearoyl ester (12.5 g, 31.2 mmol, 1 eq) inCHCl₃ (200 ml, free of ethanol). After stirring overnight the suspentionwas filtered and the filtrate was washed with brine, dried with Na₂SO₄and concentrated in vacuum. The crude material was chromatographed onsilica gel (500 g) with 19/1 to 4/1 CH₂Cl₂-MeOH as eluent, to yield theabove depicted di-ester. R_(f) (9/1 CH₂Cl₂-MeOH) 0.46. 13.8 g (70%).

¹H-NMR (250 MHz, CDCl₃) δ 7.35-7.3 (m, 5H, ArH), 5.32 (d, 1H, CH), 5.10(s, 2H, CH₂Ph), 4.33-4.18 (m, 4H, CH₂), 2.28 (t, 2H, CH₂), 2.22-2.05 (m,1H, CH), 1.65-1.50 (m, 2H, CH₂) 1.35-1.15 (m, 31H), 1.00-0.82 (m, 9H,Me).

EXAMPLE 242′,3′-Dideoxy-3′-fluoro-5′-O-[5-(L-valyloxy)-4-stearoyloxy-pentanoyl]guanosine

a) Synthesis of 2′,3′-dideoxy-3′-fluoro-5′-O-[5-(N-FMOC-L-valyoxy)-4-stearoyloxy-pentanoyl]guanosine.

A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (269 mg, 1.0 mmole),5-(N-FMOC-L-valyloxy)-4-stearoyloxy-pentanoic acid (940 mg, 1.3 mmole),DMAP (16 mg, 0.13 mmole) and HOBT (176 mg, 1.3 mmole) was coevaporatedtwo times with DMF and reduced to about 30 ml. DCC (248 mg, 1.2 mmole)was added and the mixture was stirred overnight at room temperature. Themixture was filtered and the solution was evaporated under reducedpressure. Ethyl acetate (50 ml) was added and the organic phase waswashed two times with 5% acetic acid, with 5% sodium hydrogen carbonateand with water. The organic phase was dried with sodium sulfate andevaporated under reduced pressure. The product is isolated by silica gelcolumn chromatography. Yield: 450 mg

¹H-NMR (DMSO d-6) 0.88 (m, 9H) 1.22 (m, 28H) 1.45 (m, 2H) 1.83 (m, 2H)2.21 (m, 2H) 2.37 (m, 1H) 3.90 (m, 1H) 5.36-5.58 (m, 1H) 6.18 (m, 1H)6.50 (s, 2H) 7.28-7.91 (m, 10H)

b) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-[5-(L-valyloxy)-4-stearoyloxy-pentanoyl]guanosine.

A mixture of2′,3′-dideoxy-3′-fluoro-5′-O-[5-(N-CBZ-L-valyloxy)-4-stearoyloxy-pentanoyl]guanosine(300 mg, 0.308 mmole) in 5 ml N,N-diisopropylethylamine and 5 ml DMF wasstirred for three days at room temperature. Acetic acid (5 ml) was addedand the mixture was evaporated under reduced pressure. The product wasisolated as the acetate salt by silica gel column chromatography. Yield:90 mg

¹H-NMR (DMSO d-6) 0.88 (m, 9H) 1.24 (m, 28H) 1.55 (m, 2H) 1.91 (m, 2H)2.31 (m, 2H) 2.44 (m, 1H) 2.56-3.08 (m, 2H) 3.15 (m, 1H) 4.00-4.49 (m,5H) 5.08 (m, 1H) 5.40-5.62 (m, 1H) 6.24 (m, 1H) 6.54 (s, 2H) 7.96 (s,1H)

EXAMPLE 252′,3′-Dideoxy-3′-fluoro-5′-O-[3-(L-valyloxy)-2-stearoyloxy-propanoyl]guanosine

a) Synthesis of2′,3′-Dideoxy-3′-fluoro-5′-O-[3-(N-CBZ-L-valyloxy)-2-stearoyloxy-propanoyl]guanosine.

A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (404 mg, 1.5 mmole),3-(N-CBZ-L-valyloxy)-2-stearoyloxy-propanoic acid (1.06 g, 1.75 mmole),DMAP (24 mg, 0.2 mmole) and HOBT (264 mg, 1.82 mmole) was coevaporatedtwo times with DMF and reduced to about 30 ml. DCC (372 mg, 1.8 mmole)was added and the mixture was stirred overnight at room temperature. Themixture was filtered and the solution was evaporated under reducedpressure. Ethyl acetate (50 ml) was added and the organic phase waswashed twice with 5% acetic acid, with 5% sodium hydrogen carbonate andwith water. The organic phase was dried with sodium sulfate andevaporated under reduced pressure. The product was isolated by silicagel column chromatography. Yield: 0.73 g

¹H-NMR (DMSO d-6) 0.82 (m, 9H) 1.22 (m, 28H) 1.48 (m, 2H) 2.31 (m, 2H)2.50-3.00 (m, 2H) 3.91 (m, 1H) 4.18-4.52 (m, 5H) 5.00 (s, 2H) 5.30-5.61(m, 2 H) 6.16 (m, 1H) 6.50 (s, 2H) 7.32 (m, 5H) 7.71 (m, 1H) 7.92 (s,1H) 10.18 (s, 1H)

b) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-[3-(L-valyloxy)-2-stearoyloxy-propanoyl]guanosine.

A solution of2′,3′-dideoxy-3′-fluoro-5′-O-[3-(N-CBZ-L-valyloxy)-2-stearoyloxy-propanoyl]guanosine(350 mg, 0.4 mmole) in ethyl acetate (25 ml), methanol (5 ml) and aceticacid (5 ml) was hydrogenated with palladium black (300 mg) with normalpressure for three hours. The catalyst was filtered and washed withethyl acetate and methanol. The solution was evaporated under reducedpressure and the product was isolated as the acetate salt by silica gelcolumn chromatography, Yield: 120 mg

¹H-NMR (DMSO d-6) 0.84 (m, 9H) 1.22 (m, 28H) 1.50 (m, 2H) 2.32 (m, 2H)2.50-3.00 (m, 2H) 3.07 (m, 1H) 4.21-4.59 (m, 5H) 5.38-5.59 (m, 2H) 6.17(m, 1H) 6.0 (s, 2H) 7.90 (s, 1H)

EXAMPLE 262′,3′-Dideoxy-3′-fluoro-5′-O-[3,3-bis(L-valyloxymethyl)-propionicacid]guanosine

a) Synthesis of 4,4-bis (N-CBZ-L-valyloxymethyl)-but-1-ene.

To a solution of 2-allyl-1,3-propandiol (2.32 g, 20 mmole),N-CBZ-L-valine (10.06 g, 40 mmole) and DMAP (0.488 g, 4 mmole) in 120 mldichloromethane was added DCC (9.08 g, 44 mmole) in portions and themixture was stirred overnight at room temperature. The mixture wascooled to 5° C. and the urethane was filtered. The filtrate wasevaporated and the product was isolated by silica gel columnchromatography. Yield 9.0 g

¹H-NMR (CDCl₃) 0.89 (m, 12H) 5.11 (s, 2H) 5.73 (m, 1H)

b) Synthesis of 3,3-Bis(N-CBZ-L-valyloxymethyl)-propionic acid. To acooled solution of 4,4-bis(N-CBZ-L-valyloxymethyl)-but-1-ene (14.6 g, 25mmole) and tetrabutylammonium bromide (1.3 g, 4 mmole) in 120 ml benzenewas added 100 ml water. Under strong stirring potassium permanganate(15.8 g, 100 mmole) was addded in portions and the mixture was stirredfor 2 hours between 15° C. and 20° C. A sodium bisulfite aqueoussolution was added to the slurry until the mixture was discolored. Themixture was acidified with 2N hydrochloric acid and extracted four timeswith ethyl acetate. The organic phase was washed two times with water,dried with sodium sulfate and evaporated under reduced pressure. Theproduct was isolated by silica gel column chromatography. Yield: 7.5 g

¹H-NMR (CDCl₃) 0.89 (m, 12H) 2.05 (m, 2H) 2.46 (m, 2H) 2.62 (m, 1H) 4.20(m, 6H) 5.11 (s, 4H) 5.30 (m, 2H) 7.35 (m, 10H)

c) Synthesis of 2′,3′-dideoxy-3′-fluoro-5′-O-[3,3-bis(N-CBZ-L-valyloxymethyl)-propionyl]guanosine.

A solution of 2′,3′-dideoxy-3′-fluoroguanosine (1.35 g, 5 mmole),3,3-bis(N-CBZ-L-valyloxymethyl)-propionic acid (3.6 g, 6 mmole), DMAP(0.061 g, 0.5 mmole) and HOBT (0.81 g, 6 mmole) was coevaporated twotimes with DMF and reduced to about 120 ml. DCC (1.24 g, 6 mmole) wasadded and the mixture was stirred overnight at room temperature. Themixture was filtered and the solution was evaporated under reducedpressure. Ethyl acetate (200 ml) was added and the organic phase washedtwice with 5% acetic acid, 5% sodium hydrogen carbonate and water. Theorganic phase was dried with sodium sulfate and evaporated under reducedpressure. The product was isolated by silica gel column chromatography.Yield: 2.7 g

¹H-NMR (DMSO d-6) 0.88 (m, 12H) 2.00(m, 2H) 2.50-3.00 (m, 2H) 3.90-4.43(m, 10H) 5.08 (s, 4H) 5.32-5.59 (m, 1H) 6.17 (m, 1H) 6.50 (s, 2H) 7.28(m, 10H) 7.72 (m, 2H) 7.90 (s, 1H)

d) Synthesis of2′,3′-Dideoxy-3′-fluoro-5′-O-[3,3-bis(L-valyloxymethyl)-propionicacid]guanosine.

A solution of2′,3′-dideoxy-3′-fluoro-5′-O-[3,3-bis(N-CBZ-L-valyloxymethyl)-propionyl]guanosine(2.6 g, 3.1 mmole) in 80 ml ethyl acetate, 20 ml methanol and 20 mlacetic acid was hydrogenated with palladium black (0.3 g) for two hoursunder normal pressure, The catalyst was filtered and washed with ethylacetate and methanol. The solution was evaporated under reduced pressureand the product was isolated as the bisacetate salt by silica gel columnchromatography. Yield: 1.2 g

¹H-NMR (DMSO d-6) 0.90 (m, 12H) 1.78 (m, 2H) 2.50-3.00 (m, 2H) 3.09 (m,2H) 4.02-4.45 (m, 8H) 5.34-5.59 (m, 1H) 6.17 (m, 1H) 6.62 (s, 2H) 7.88(s, 1H)

EXAMPLE 272′,3′-Dideoxy-3′-fluoro-5′-O-[3-(L-valyloxymethyl)-4-stearoyloxy-butoxycarbonyl]guanosine

a) Synthesis of2′,3′-Dideoxy-3′-fluoro-5′-O-[3-(N-CBZ-L-valyloxymethyl)-4-stearoyloxy-butoxycarbonyl]guanosine.

To a solution of 2′,3′-dideoxy-3′-fluoroguanosine (269 mg, 1.0 mmole inabsolute DMF were added pyridine (198 mg, 2.5 mmole) and a solution of3-(N-CBZ-L-valyloxymethyl)-4-stearoyloxy-butoxycarbonyl chloride (750mg, 1.1 mmole) in 5 ml dichloromethane. The mixture was stirred forthree days at room temperature. The solution was evaporated underreduced pressure and the product was isolated by silica gel columnchromatography. Yield: 120 mg

¹H-NMR (DMSO d-6) 0.88 (m 9H) 1.24 (m, 28H) 5.08 (s, 2H) 6.24 (m, 1H)8.00 (s, 1H)

b) Synthesis of2′,3′-Dideoxy-3′-fluoro-5′-O-[3-(L-valyloxymethyl)-4-stearoyloxy-butoxycarbonyl]guanosine.

A mixture of2′,3′-dideoxy-3′-fluoro-5-O-[3-(N-CBZ-L-valyloxymethyl)-4-stearoyloxy-butoxycarbonyl]guanosinein 15 ml ethyl acetate, 2 ml methanol and 2 ml acetic acid washydrogenated with palladium black (40 mg) under normal pressure for twohours. The catalyst was filtered and washed with ethyl acetate andmethanol. The solution was evaporated and the product isolated as theacetate salt by silica gel column chromatography, Yield: 78 mg

¹H-NMR (DMSO d-6) 0.87 (m, 9H) 1.22 (m, 28H) 1.48 (m, 2H) 1.68 (m, 2H)2.12 (m, 1H) 2.26 (m, 2H) 2.50-3.00 (m, 2H) 4.00-4.42 (m, 10H) 5.34-5.58(m, 1H) 6.18 (m, 1H) 6.52 (s, 2H) 7.82 (s, 1H)

EXAMPLE 28 2′,3′-Dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)stearoyl]guanosine

a) Synthesis of benzyl 2-hydroxystearate.

To a stirred solution of DL-2-hydroxystearic acid (3.0 g, 10 mmole) in20 ml dry DMF was added potassium tert-butoxide (1.23 g, 11 mmole) andthe mixture was stirred for one hour at 60° C. Benzyl bromide (2.14 g,12.5 mmole) was added and the mixture was stirred for six hours at 80°C. The mixture was evaporated under reduced pressure and 100 ml ethylacatate was added. The organic phase was separated and washed four timeswith water. The organic phase was dried with sodium sulfate andconcentrated in vacuo. The product was isolated by silica gel columnchromatography. Yield: 3.3 g

¹H-NMR (CDCl₃) 0.88 (m, 3H) 1.26 (m, 28H) 1.62 (m, 2H) 4.20 (m, 1H) 5.20(s, 2H) 7.36 (m, 5H)

b) Synthesis of benzyl-2-(N-FMOC-L-valyloxy)stearate.

To a solution of benzyl-2-hydroxystearate (3.2 g, 8.2 mmole),N-FMOC-L-valine (3.4 g, 10 mmole) and DMAP (0.12 g, 1 mmole) in 80 mldichloromethane was added a solution of DCC (2.5 g, 12 mmole) and themixture was stirred overnight at room temperature. The mixture wascooled to 5° C. and the urethane was filtered. The filtrate wasevaporated and the product was isolated by silica gel columnchromatography. Yield: 4.5 g

¹H-NMR (CDCl₃) 0.90 (m, 6H) 1.26 (m, 6H) 1.82 (m, 2H) 2.16 (m, 1H) 4.21(m, 1H) 4.36 (m, 2H) 5.10 (m, 1H) 5.18 (s, 2H) 5.28 (m, 1H) 7.20-7.80(m, 13H)

c) Synthesis of 2-(N-FMOC-L-valyloxy) stearic acid.

A solution of benzyl-2-(N-FMOC-L-valyloxy)stearate (4.4 g, 6.2 mmole) in50 ml ethyl acetate was hydrogenated with 10% palladium on charcoal (0.5g) with normal pressure for two hours. The catalyst was filtered andwashed with ethyl acetate and 1,4-dioxane. The solution was evaporatedunder reduced pressure and the product was isolated by silica gel columnchromatography. Yield: 3.4 g

¹H-NMR (CDCl₃) 0.88 (m, 6H) 1.26 (m, 28H) 1.82 (m, 2H) 2.28 (m, 1H) 4.20(m, 1H) 4.40 (m, 2H) 5.00 (m, 1H) 5.41 (m, 1H) 7.26-7.82 (m, 8H)

d) Synthesis of2′,3′-Dideoxy-3′-fluoro-5′-O-[2-(N-FMOC-L-valyloxy)stearoyl]guanosine.

A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (404 mg, 1.5 mmole),2-(N-FMOC-L-valyloxy)stearic acid (1.24 g, 2 mmole), DMAP (24 mg, 0.2mmole) and HOBT (264 mg, 1.95 mmole) was coevaporated two times with DMFand reduced to about 30 ml. DCC (372 mg, 1.8 mmole) was added and themixture was stirred overnight at room temperature. The mixture wasfiltered and the solution was evaporated under reduced pressure. Ethylacetate (50 ml) was added and the organic phase washed twice with 5%acetic acid, with 5% sodium hydrogen carbonate and with water. Theorganic phase was dried with sodium sulfate and evaporated under reducedpressure. The product was isolated as the acetate salt by silica gelcolumn chromatography. Yield: 1.2 g

¹H-NMR (DMSO d-6) 0.80-0.90 (m, 9H) 1.22 (m, 28H) 2.12 (m, 1H) 2.50-3.00(m, 2H) 3.98 (m, 1H) 4.96 (m, 1H) 6.17 (m, 1H) 6.50 (s, 2H) 7.32-7.95(m, 10H)

e) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-stearoyl]guanosine.

To a solution of 2′,3′-dideoxy-3′-fluoro-5′-O-[2-(N-FMOC-L-valyloxy)stearoyl]guanosine (800 mg, 0.89 mmole) in 15 ml DMF was added DBU (1.35g, 8.9 mmole) and the mixture was stirred for 5 minutes at roomtemperature. Acetic acid (2 ml) was added and the mixture was evaporatedunder reduced pressure. Water (20 ml) were added and the mixture wasextracted three times with dichloromethane. The organic phase was driedwith sodium sulfate and evaporated under reduced pressure. The productwas isolated by silica gel column chromatography. Yield: 165 mg

¹H-NMR (DMSO d-6) 0.87 (m, 9H) 1.22 (m, 28H) 1.70 (m, 2H) 1.88 (m, 1H)2.50-3.00 (m, 2H) 3.20 (m, 1H) 4.32 (m, 3H) 4.94 (m, 1H) 5.32-5.54 (m,1H) 6.14 (m, 1H) 6.49 (s , 2H) 7.89 (s, 1H)

EXAMPLE 292′,3′-Dideoxy-3′-fluoro-5′-O-3-[1,3-bis-(L-valyloxy)-2-propyloxycarbonylpropanoyl]guanosine

a) Synthesis of 1,3-dibenzyloxy-2-propyl succinate monoester.

A solution of 1,3-dibenzyloxypropan-2-ol (6.8 g, 25 mmole) and succinicanhydride (7.5 g, 75 mmole) and DMAP (12.2 g, 100 mmole) was stirred forone hour at 60° C. The mixture was evaporated under reduced pressure,acidified with 2N HCl and extracted two times with ethyl actate. Thecombined organic phase was washed three times with water, dried withsodium sulfate and evaporated under reduced pressure. The product wasisolated by silica gel column chromatography. Yield: 7.8 g

b) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-[3-(1,3-dibenzyloxy-2-propyloxycarbonyl)-propanoyl]guanosine.

A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (1.61 g, 6 mmole), HOBT(0.972 g, 7.2 mmole), DMAP (73.3 mg, 0.6 mmole) and1,3-dibenzyloxy-2-propyl succinate monoester (2.68 g, 7,2 mmole) wascoevaporated two times with DMF and reduced to about 150 ml. DCC (1.55g, 7.5 mmole) was added and the mixture was stirred 72 hours at roomtemperature. The mixture was filtered and the solution was evaporatedunder reduced pressure. Ethyl acetate (200 ml) was added and the organicphase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate andwater. The organic phase was dried with sodium sulfate and evaporatedunder reduced pressure. The product was isolated by silica gel columnchromatography. Yield: 3.3 g

c) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-[3-(1,3-dihydroxy-2-propyloxycarbonyl)propanoyl]guanosine.

A solution of2′,3′-dideoxy-3′-fluoro-5′-O-[3-(1,3-dibenzyloxy-2-propyloxycarbonyl)propanoyl]guanosine (3.2 g, 5.13 mmole) in 50 ml ethyl acetate,50 ml methanol and 10 ml acetic acid was hydrogenated with palladiumblack (0.6 g) under 40 psi overnight. The catalyst was filtered andwashed with methanol, The solution was evaporated under reduced pressureand the product was isolated by silica gel column chromatography. Yield:1.64 g

d) Synthesis of 2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1,3-Bis(N-CBZ-L-valyloxy)-2-propyloxycarbonyl]propanoyl}guanosine.

A mixture of 2′,3′-dideoxy-3′-fluoro-5′-O-[3-(1,3-dihydroxy-2-propyloxycarbonyl)-propanoyl]guanosine (1.93 g, 2.93 mmole), N-CBZ-L-valine (1.76g, 7 mmole), HOBT (0.95 g, 7 mmole) and DMAP (85.5 mg, 0.7 mmole) wascoevaporated two times with DMF and reduced to about 60 ml. DCC (1.55 g,7.5 mmole) was added and the mixture was stirred overnight at roomtemperature. The mixture was warmed for four hours at 60° C. and thencooled to about 10° C. The mixture was filtered and the solution wasreduced under reduced pressure. Ethyl acetate (150 ml) was added and theorganic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate andevaporated under reduced pressure. The product was isolated by silicagel column chromatography. Yield: 1.6 g.

e) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1,3-bis-(L-valyloxy)-2-propyloxycarbonyl]-propanoyl}guanosine.

A solution of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1,3-bis-(N-CBZ-L-valyloxy)-2-propyloxycarbonyl]-propanoyl}guanosine(1.6g, 1.75 mmole) in 80 ml ethyl acetate, 20 ml methanol and 20 ml aceticacid was hydrogenated with palladium black (0.3 g) for two hours at roomtemperature and normal pressure. The catalyst was filtered and washedwith methanol. The solution was evaporated under reduced pressure andthe product was isolated as the diacetate salt by silica gel columnchromatography. Yield: 1.02 g

¹H-NMR (DMSO d-6) 0.84 (m, 12H) 1.85(m, 2H) 2.58 (m, 4H) 2.60-3.10 (m,2H) 3.11 (m, 2H) 3.61-4.39 (m, 7H) 5.19 (m, 1H) 5.35-5.56 (m, 1H) 6.16(m, 1H) 6.62 (s, 2H) 7.89 (s,1H)

EXAMPLE 302′,3′-Dideoxy-3′-fluoro-5′-O-{3-[1-(L-valyloxy)-3-hydroxy-2-propyloxycarbonyl]-propanoyl}guanosine

a) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1-(N-CBZ-L-valyloxy)-3-hydroxy-2-propyloxycarbonyl]-propanoyl}guanosine.

A mixture of 2′,3′-dideoxy-3′-fluoro-5′-O-[3-(1,3-dihydroxy-2-propyloxycarbonyl)-propanoyl]guanosine (1.3 g, 2.93 mmole), N-CBZ-L-valine (1.00g, 4 mmole), HOBT (0.54 g, 4 mmole) and DMAP (48.8 mg, 0.4 mmole) wascoevaporated two times with DMF and reduced to about 60 ml. DCC (0.91 g,4.4 mmole) was added and the mixture was stirred for 72 hours at roomtemperature. The mixture was filtered and the solution evaporated underreduced pressure. Ethyl acetate (150 ml) was added and the organic phasewashed twice with 5% acetic acid, 5% sodium hydrogen carbonate andwater. The organic phase was dried with sodium sulfate and evaporatedunder reduced pressure. The product was isolated by silica gel columnchromatography. Yield: 0.99 g

b) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1-(L-valyloxy)-3-hydroxy-2-propyloxycarbonyl]-propanoyl}guanosine.

A solution of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1-(N-CDZ-L-valyloxy)-3-hydroxy-2-propyloxycarbonyl)-propanoyl}guanosine(0.82 g, 1.21 mmole) in 30 ml ethyl acetate, 15 ml methanol and 15 mlacetic acid was hydrogenated with palladium black (0.15 g) for two hoursat room temperature and normal pressure. The catalyst was filtered andwashed with methanol. The solution was evaporated under reduced pressureand the product was isolated as th acetate salt by silica gel columnchromatography. Yield: 0.5 g

¹H.NMR (DMSO d-6) 0.84 (m, 6H) 1.86 (m, 1H) 2.58 (m, 4H) 2.63-3.02 (m,2H) 3.10-4.38 (m, 9H) 5.34-5.55 (m, 1H) 6.16 (m, 1H) 6.56 (s, 2H) 7.90(s, 1H)

EXAMPLE 31 5′-valyl-2′,3′-dideoxy-3′-fluoroguanosine

To a solution of 2′,3′-dideoxy-3′-fluoroguanosine (810 mg, 3 mmole) and4-dimethylaminopyridine (73 mg, 0.6 mmole), N-CBz-L-valine (1.5 g, 6mmole) and 1-hydroxybenzotriazole (810 mg, 6 mmole) in DMF (20 ml) wasadded DCC (1.36 g, 6.6 mmole). After 72 h, the reaction mixture wasfiltered and concentrated in vacuo.5′-(N-CBz-L-valyl)-2′,3′-dideoxy-3′-fluoroguanosine was isolated bysilica gel column chromatography (1.15 g).

This intermediate (503 mg, 1 mmole) was dissolved in a mixed solvent ofethyl acetate (10 ml), methanol (20 ml) and acetic acid (2 ml). To themixture was added palladium black (100 mg) and the reaction mixture waskept under hydrogen at atmospheric pressure for 3 h. After filtrationand concentration, the titled product was isolated by silica gel columnchromatography (370 mg).

¹H-NMR (DMSO d-₆): 7.94 (s, 1H), 6.52 (s, 2 H), 6.17 (dd, 1H), 5.47 (dd,1H), 4.15 (m, 3H), 3.15 (d, 1 H), 3.01-2.62 (m, 2H), 1.80 (m, 1H), 0.82(dd, 6 H).

EXAMPLE 322′,3′-Dideoxy-3′-fluoro-5-O-[2-(-L-valyloxy)-propionyl]guanosine

a) Synthesis of 4-methoxybenzyl-2-hydroxypropionate.

To a stirred solution of DL -2 hydroxypropionic acid (9.0 g, 100 mmole)in 100 ml dry DMF was added potassium tert-butoxide (12.34 g, 110 mmole)and the mixture was stirred for one hour at 60° C. 4-methoxybenzylchloride (18.8 g 120 mmole) was added and the mixture was stirred foreight hours at 60° C. The mixture was evaporated under reduced pressureand 250 ml ethyl acatate was added. The organic phase was washed fourtimes with water. The organic phase was dried with sodium sulfate andconcentrated in vacuo. Yield: 16.8 g

¹H-NMR (CDCl₃) 1.40 (m, 3H) 3.81 (s, 3H) 4.26 (m, 1H) 5.14 (s, 2H) 6.90(d, 2H) 7,28 (d, 2H)

b) Synthesis of 4-methoxybenzyl-2-(N-CBZ-L-valyloxy)propionate.

To a solution of 4-methoxybenzyl-2-hydroxypropionate (4.2 g, 20 mmole),N-CBZ-L-valine (5.02 g, 20 mmole) and DMAP (0.24 g, 2 mmole) in 100 mldichloromethane was added a solution of DCC (4.54 g, 22 mmole) and themixture was stirred overnight at room temperature. The mixture wascooled to 5° C. and the urethane was filtered. The filtrate wasevaporated and the product was isolated by silica gel columnchromatography. Yield: 7.9 g

¹H-NMR (CDCl₃) 0.88 (m, 6H) 1.50 (m, 3H) 2.26 (m, 1H) 3.81 (s, 3H) 4.34(m, 1H) 5.04-5.30 (m, 6H) 6.88 (d, 2H) 7.26 (m, 7H)

c) Synthesis of 2-(N-CBZ-L-valyloxy)-propionic acid.

To a solution of 4-methoxybenzyl-2-(N-CBZ-L-valyloxy)-propionate (7.8 g,17.5 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid(10 ml) and the solution was stirred for one hour at room temperature.The solution was evaporated under reduced pressure and the product wasisolated by silica gel column chromatography. Yield: 5.0 g

¹H-NMR (CDCl₃) 0.94 (m, 6H) 1.56 (d, 3H) 2.30 (m, 1H) 4.42 (m, 1H)5.12-5.30 (m, 4H) 7.28 (m, 5H)

d) Synthesis of2′,3′-dideoxy-3′-fluoro-5-O-[2-(N-CBZ-L-valyloxy)-propionyl]guanosine.

A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (404 mg, 1.5 mmole),2-(N-CBZ-L-valyloxy)-propionic acid (0.582 g, 1.8 mmole), DMAP (22 mg,0.18 mmole) and HOBT (243 mg, 1.8 mmole was coevaporated two times withDMF and reduced to about 30 ml. DCC (412 mg, 2.0 mmole) was added andthe mixture was stirred overnight at room temperature. The mixture wasfiltered and the solution was evaporated under reduced pressure. 100 mlethyl acetate was added and the organic phase was washed twice with 5%acetic acid, with 5% sodium hydrogen carbonate and with water. Theorganic phase was dried with sodium sulfate and evaporated under reducedpressure. The product was isolated by silica gel column chromatography.Yield: 0.72 g

¹H-NMR (DMSO d-6) 0.92 (m, 6H) 1.40 (d, 3H) 2.10 (m, 1H) 2.50-3.06 (m,2H) 4.03 (m, 1H) 4.20-4.44 (m, 3H) 5.04 (s, 2H) 5.12 (m, 1H) 5.44-5.58(m, 1H) 6.18 (t, 1H) 6.52 (s, 2H) 7.36 (m, 5H) 7.70 (d, 2H) 7.92 (s, 1H)

e) Synthesis of2′,3′-dideoxy-3′-fluoro-5-O-[2-(L-valyloxy)-propanoyl]guanosine

A solution of2′,3′-dideoxy-3′-fluoro-5-O-[2-(N-CBZ-L-valyloxy)-propanoyl]guanosine(0.6 g, 1.04 mmole) in 20 ml ethyl acetate, 10 ml methanol and 10 mlacetic acid was hydrogenated with palladium black (0.1 g) for two hoursat room temperature and normal pressure. The catalyst was filtered andwashed with methanol. The solution was evaporated under reduced pressureto yield the title compound as the acetate salt. Yield: 0.5 g

¹H-NMR (DMSO d-6) 0.88 (m, 6H) 1.40 (d, 3H) 1.92 (m, 4H) 2.52-3.04 (m,2H) 3.18 (m, 1H) 4.18-4.42 (m, 3H) 5.06 (m, 1H) 5.32-5.58 (m, 2H) 6.18(m, 1H) 6.52 (s, 2H) 7.90 (s, 1H)

EXAMPLE 332′,3′-Dideoxy-3′-fluoro-5′-O-3-[2,3-bis-(L-valyloxy)-1-propyloxycarbonyl]-propanoylguanosine.

a) Synthesis of 4-methoxybenzyl succinate monoester.

To a mixture of succinic anhyride (75 g, 750 mmole) and 4-methoxybenylalcohol (69.1 g, 500 mmole) in 1,4-dioxane (300 ml) was added pyridine(79.1 g, 1000 mmole) and the mixture was stirred for five hours at 80°C. The mixture was evaporated under reduced pressure and 600 ml of ethylacetate and 60 ml of acetic acid were added. The organic phase waswashed three times with water, dried with sodium sulfate and evaporatedunder reduced pressure. The product was recrystallized from toluene.Yield: 104 g.

¹H-NMR (DMSO d-6) 2.48 (m, 4H) 3,72 (s, 3H) 5.00 (s, 2H) 6.90 (d, 2H)7.28 (d, 2H)

b) Synthesis of succinic acid 2,3-dihydroxy-propyl ester,4-methoxybenzyl ester.

To a solution of glycerol (23.0 g, 250 mmole), 4-methoxybenzyl succinatemonoester (5.96 g, 25 mmole) and DMAP (0.36 g, 3 mmole) in DMF (200 ml)was added DCC (6.2 g 30 mmole) and the mixture was stirred overnight atroom temperature. The mixture was evaporated under reduced pressure and150 ml dichloromethane was added. The mixture was filtered and thesolution washed twice with water. The water phase was extracted twotimes with dichloromethane and the combined organic phases were driedwith sodium sulfate. The solution was evaporated under reduced pressureand the product was isolated by silica gel column chromatography. Yield:3.0 g

¹H-NMR (CDCl₃) 2.65 (m, 4H) 3.61 (m, 2H) 3.80 (s, 3H) 3.90 (m, 1H) 4.18(m, 2H) 5.05 (s, 2H) 6.89 (d, 2H) 7.26 (d, 2H)

c) Synthesis of succinic acid 2,3-bis-(N-CBZ-L-Valyloxy)-propyl ester,4-methoxybenzyl Ester.

To a stirred solution of succinic acid 2,3-dihydroxy-propyl ester,4-methoxybenzyl ester (2.9 g, 9.28 mmole), N-CBZ-L-valine (5.03 g, 20mmole) and DMAP (0.244 g, 2 mmole) in dichlorometane (60 ml) was addedDCC (4.5 g, 22 mmole) and the mixture was stirred overnight at roomtemperature. The mixture was filtered and the solution was evaporatedunder reduced pressure. The product was isolated by silica gel columnchromatography. Yield: 2.5 g

¹H-NMR (CDCl₃) 0.90 (m, 12H) 2,16 (m, 2H) 2.62 (m, 4H) 3.80 (s, 3H) 4.32(m, 4H) 5.05-5.52 (m, 9H) 6.89 (d, 2H) 7.30 (m, 12H)

d) Synthesis of succinic acid 2,3-bis-(N-CBZ-L-valyloxy)propyl ester.

To a solution of the above intermediate (2.3 g, 2.95 mmole) indichloromethane (25 ml) was added trifluoroacetic acid (2.5 ml) and thesolution was stirred for two hours at room temperature. The solution wasevaporated under reduced pressure and the product was isolated by silicagel column chromatography. Yield: 1,8 g

¹H-NMR (CDCl₃) 0.92 (m, 12H) 2.12 (m, 2H) 2.64 (m, 4H) 4.32 (m, 4H) 5.10(s, 4H) 5.22-5.50 (m, 3H) 7.34 (m, 10H)

e) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[2,3-bis(N-CBZ-L-valyloxy)-1-propyloxycarbonyl]propanoyl}guanosine.

A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (0.538 g, 2 mmole), HOBT(0.327 g, 2.42 mmole), DMAP(29.3 mg, 0.24 mmole) and succinic acid2,3-bis-(N-CBZ-L-valyloxy)-1-propyl ester (1.6 g, 2.42 mmole) wascoevaporated two times with DMF and reduced to about 50 ml. DCC (0.536g, 2.6 mmole) was added and the mixture was stirred 72 hours at roomtemperature. The mixture was filtered and the solution was evaporatedunder reduced pressure. 100 ml of ethyl acetate was added and theorganic phase washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with sodium sulfate andevaporated under reduced pressure. The product was isolated by silicagel column chromatography. Yield: 0.65 g.

¹H-NMR (DMSO-d6) 0.88 (m, 12H) 2.08 (m, 2H) 2.58-3.04 (m, 6H) 3.92 (m,2H) 4.10-4.46 (m, 7H) 5.00 (s, 4H) 5.22 (m, 1H) 5.32-5.56 (m, 1H) 6.17(m, 1H) 6.50 (s, 2H) 7.32 (m, 10H) 7.70 (d, 2H) 7.92 (s, 1H)

f) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[2,3-bis-(L-valyloxy)-1-propyloxycarbonyl]-propanoyl}guanosine.

A solution of the intermediate immediately above (0.57 g, 0.626 mmole)in 20 ml ethyl acetate, 10 ml methanol and 10 ml acetic acid washydrogenated with palladium black (0.1 g) for two hours at roomtemperature and normal pressure. The catalyst was filtered and washedwith methanol. The solution was evaporated under reduced pressure andthe product was isolated by silica gel column chromatography. Theproduct was dissolved in dichloromethane and 1M hydrogen chloride inether (1.1 ml) was added. The mixture was evaporated under reducedpressure and dried in vacuo to yield the title compound as thedihydrochloride salt. Yield: 0.37 g

¹H-NMR (DMSO d-6) 0.92 (m, 12H) 2.12 (m, 2H) 2.58-3.04 (m, 6H) 3.75 (m,2H) 4.16-4.50 (m, 7H) 5.19-5.60 (m, 2H) 6.18 (m, 1H) 6.76 (s, 2H) 7.92(s, 1H)

EXAMPLE 342′,3′-Dideoxy-3′-fluoro-5′-O-3-[1,3-bis-(L-valyloxy)-2-propyloxycarbonyl]propanoylguanosine, dihydrochloride salt.

a) Synthesis of succinic acid 1,3-dibromo-2-propyl ester,4-methoxybenzyl ester.

To a solution of 1,3-dibromopropan-2-ol (21.8 g, 100 mmole), succinicacid 4-methoxybenzyl ester (28.6 g, 120 mmole) and DMAP (1.22 g, 10mmole) in dichloromethane (400 ml) was added DCC (24.8 g, 120 mmole) inportions at about 10° C. The mixture was stirred overnight at roomtemperature and cooled to about 5° C. The mixture was filtered and thesolution was evaporated under reduced pressure. 600 ml of ethyl acetatewas added and the organic phase was washed twice with 5% acetic acid, 5%sodium hydrogen carbonate and water. The solution was dried with sodiumsulfate and evaporated under reduced pressure. The product was isolatedby silica gel column chromatography. Yield: 34.8 g.

¹H-NMR (CDCl₃) 2.69 (m, 4H) 3.57 (m, 4H) 3.81 (s, 3H) 5.07 (s, 2H) 5.14(m, 1H) 6,88 (d, 2H) 7.26 (d, 2H)

b) Synthesis of succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester,4-methoxybenzyl ester.

To a solution of N-CBZ-L-valine (58.5 g, 232.8 mmole) in dried DMF (300ml) was added potassium-tert-butoxide (24,68 g, 220 mmole) and themixture was stirred for one hour at room temperature. A solution ofsuccinic acid 1,3-dibromo-2-propyl ester, 4-methoxybenzyl ester (34 g,77.6 mmole) in dried DMF (50 ml) was added and the mixture was stirredfor eighteen hours at 60° C. The potassium bromide was filtered and thesolution was evaporated under reduced pressure. 600 ml of ethyl acetatewas added and the organic phase washed twice with 5% sodium hydrogencarbonate and with water. The organic phase was dried with sodiumsulfate and evaporated under reduced pressure. The product was isolatedby silica gel column chromatography. Yield: 45 g

¹H-NMR (CDCl₃) 0.90 (m, 12H) 2.16 (m, 2H) 2.61 (m, 4H) 3.80 (s, 3H )4.12-4.42 (m, 6H) 5.02 (s, 2H) 5.10 (s, 4H) 5.43 (m, 3H) 6.88 (d, 2H)7.32 (m, 12H)

c) Synthesis of succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester.

To a cooled solution of the intermediate immediately above (44.5 g, 57.1mmole) in dichloromethane (500 ml) was added trifluoroacetic acid (50ml) between 5° C. and 10° C. and the solution was stirred for two hoursat 10° C. The solution was evaporated under reduced pressure and twotimes coevaporated with toluene. 400 ml of ethanol was added and themixture was stirred for 30 minutes at 40° C. The mixture was cooled andthe biproduct filtered. The solution was evaporated under reducedpressure and the product was isolated by silica gel columnchromatography. Yield: 33 g

¹H-NMR (DMSO-d6) 0.88 (m, 12H) 2.04 (m, 2H) 2.46 (m, 4H) 3.94-4.40 (m,6H) 5.02 (s, 4H) 5.18 (m, 1H) 7.32 (m, 10H) 7,74 (d, 2H)

d) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1,3-bis-(N-CBZ-L-valyloxy)-2-propyloxycarbonyl]propanoyl}guanosine.

A mixture of 2′,3′dideoxy-3′-fluoroguanosine (17.8 g, 66 mmole), HOBT(10.64 g, 78.8 mmole), succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-2-propylester (52 g, 78.8 mmole) and DMAP (0.96 g, 7.88 mmole) was coevaporatedtwo times with DMF and redued to about 500 ml. DCC (17.3 g, 84 mmole)was added and the mixture was stirred overnight at room temperature. Themixture was warmed for six hours at 60° C. and then cooled to about 10°C. The mixture was filtered and the solution was reduced under reducedpressure. 1200 ml of ethyl acetate was added and the organic phase waswashed twice with 5% acetic acid, 5% sodium hydrogen carbonate andwater. The organic phase was dried with sodium sulfate and evaporatedunder reduced pressure. The product was isolated by silica gel columnchromatography. Yield: 42 g.

¹H-NMR (DMSO-d6) 0.90 (m, 12H) 2.02 (m, 2H) 2.5-3.02 (m, 6H) 3.94 (m,2H) 4.22 (m, 7H) 5.02 (s, 4H) 5.18 (m, 1H) 5.22-5.50 (m, 1H) 6.16 (m,1H) 6.50 (s, 2H) 7.32 (m, 10H) 7.72 (d, 2H 7.92 (s, 1H)

e) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1,3-bis-(L-valyloxy)-2-propyloxycarbonyl]-propanoyl}guanosineDihydrochloride Salt.

A solution of2′,3′-dideoxy-3′-fluoro-5′-O-{3-[1,3-bis-(N-CBZ-L-valyloxy)-2-propyloxycarbonyl]propanoyl}guanosine(5.0, 5.9 mmole) in 75 ml ethyl acetate and 75 ml methanol washydrogenated with palladium on activated carbon 10% Pd (1 g) one hour atroom temperature and normal pressure. The catalyst was filtered andwashed with methanol. The solution was evaporated under reducedpressure. The product was dissolved in dichloromethane and a solution of1M hydrogen chloride in ether (6 ml) was added, while cooling. Themixture was evaporated under reduced pressure. Yield: 3.5 g

¹H-NMR (DMSO d-6) 0.94 (m, 12H) 2.18 (m, 2H) 2.5-3.04 (m, 6H) 4.20-4.54(m, 7H) 5.24 (m, 1H) 5.34-5.64 (m, 1H) 6.22 (m, 1H) 6.92 (s, 2H) 8.30(s, 1H) 8.62 (s, 6H)

EXAMPLE 35 Alternative Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-3-[1,3-bis-(L-valyloxy-2-propyloxycarbonyl]propanoylguanosine

a) Synthesis of succinic acid 1,3-dibromo-2-propyl ester,1,1-dimethylethyl ester.

To a solution of 1,3-dibromopropan-2-ol (10.9 g 50 mmole), succinic acid1,1-dimethylethyl ester (J. Org. Chem 59 (1994) 4864) (10.45 g, 60mmole) and DMAP (0.61 g, 5 mmole) in dichloromethane (180 ml) was addedDCC (12.4 g, 60 mmole) in portions at about 10° C. The mixture wasstirred overnight at room temperature and cooled to about 5° C. Themixture was filtered and the solution was evaporated under reducedpressure. 250 ml ethyl acetate was added and the organic phase waswashed twice with 5% citric acid, 5% sodium hydrogen carbonate andwater. The solution was dried with sodium sulfate and evaporated underreduced pressure. The product was distilled in vacuo. (bp 0,5 135-140°C.) Yield: 16.8 g

¹H-NMR (CDCl₃) 1.45 (s, 9H) 2.58 (m, 4H) 3.61 (m, 4H) 5.12 (m, 1H)

b) Synthesis of succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester,1,1-dimethylethyl ester.

To a solution of N-CBZ-L-valine (18.85 g, 75 mmole) in dried DMF (100ml) was added potassium tert-butoxide (7.85 g, 70 mmole) and the mixturewas stirred for one hour at room temperature. A solution of succinicacid 1,3-dibromo-2-propyl ester, 1,1-dimethylethyl ester (9.35 g, 25mmole) in dried DMF (20 ml) was added and the mixture was stirred foreighteen hours at 60° C. The potassium bromide was filtered and thesolution evaporated under reduced pressure. 300 ml of ethyl acetate wereadded and the organic phase washed twice with 5% sodium hydrogencarbonate and with water. The organic phase was dried with sodiumsulfate and evaporated under reduced pressure. The product was isolatedby silica gel column chromatography. Yield: 14 g

¹H-NMR (CDCl₃) 0.90 (m, 12H) 1.42 (s, 9H) 2.14 (m, 2H) 2.52 (m, 4H) 4.32(m, 6H) 5.10 (s, 4H) 5.32 (m, 3H) 7.26 (m, 10H)

c) Synthesis of 1,3-bis-(N-CBZ-L-valyloxy )-2-propyl succinatemonoester.

To a cooled solution of succinic acid1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester, 1,1-dimethylethyl ester (13g, 18.18 mmole) in dichloromethane (100 ml) was added trifluoroaceticacid (20 ml) and the solution was stirred for six hours at roomtemperature. The solution was evaporated under reduced pressure. 200 mlethyl acetate was added and the organic phase was washed with 5% sodiumhydrogen carbonate and water. The solution was evaporated under reducedpressure. Yield: 11.7 g

¹H-NMR (DMSO-d6) 0.88 (m, 12H) 2.04 (m, 2H) 2.46 (m, 4H) 3.94-4.40 (m,6H) 5.02 (s, 4H) 5.18 (m, 1H) 7.32 (m, 10H) 7.74 (d, 2H)

d) Synthesis of2′,3′-dideoxy-3′-fluoro-5′-O-3-[1,3-bis-(L-valyloxy)-2-propyloxycarbonyl]propanoylguanosine

The intermediate from step c) is esterified to FLG as shown in example34 step d) and the N-protecting groups on the valyl moieties removed byconventional techniques, such as shown in Example 35 step e) or Example29 step e).

EXAMPLE 362′,3′-Dideoxy-3′-fluoro-5′-O-[(S)-(+)2-L-valyloxy)-propanoyl]guanosine

a)2′,3′-Dideoxy-3′-fluoro-5-O-[(S)-(+)-2-(N-CBZ-L-valyloxy)propionyl]guanosine.

A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (2.69 g, 10 mmole),(S)-(+)-2-(N-CBZ-L-valyloxy)-propionic acid (4.2 g, 13 mmole), DMAP(0.244 g, 2 mmole) and HOBT (1.76 g, 13 mmole) was coevaporated twotimes with DMF and reduced to about 150 ml. DCC (3.1 g, 15 mmole) wasadded and the mixture was stirred overnight at room temperature and twohours at 60° C. The mixture was filtered and the solution was evaporatedunder reduced pressure. 300 ml ethyl acetate was added and the organicphase was washed twice with 5% acetic acid, with 5% sodium hydrogencarbonate and with water. The organic phase was dried with sodiumsulfate and evaporated under reduced pressure. The product was isolatedby silica gel column chromatography. Yield: 5.0 g=87%

¹H-NMR (DMSO d-6) 0.92 (m, 6H) 1.40 (d, 3H) 2.10 (m, 1H) 2.55-3.06 (m,2H) 4.03 (m, 1H) 4.20-4.44 (m, 3H) 5.04 (s, 2H) 5.12 (m, 1H) 5.44-5.58(m, 1H) 6.18 (t, 1H) 6.52 (s, 2H) 7.36 (m, 5H) 7.70 (d, 2H) 7.92 (s, 1H)

b)2′,3′-Dideoxy-3′-fluoro-5′-O-[(S)-(+)2-(L-valyloxy)propanoyl]guanosine

A solution of2′,3′-dideoxy-3′-fluoro-5-O-[(S)-(+)-2-(-CBZ-L-valyloxy)propanoyl]guanosine(3.0 g, 5.22 mmole) in 120 ml ethyl acetate and 40 ml acetic acid washydrogenated with palladium black (1.0 g) for 2.5 hours at roomtemperature and 40 psi. The catalyst was filtered and washed with ethylacetate and acetic acid. The solution was evaporated under reducedpressure to yield the hydrochloride salt. Yield: 2.4 g=95%

¹H-NMR (DMSO d-6+D₂O) 0.88 (m, 6H) 1.42 (d, 3H) 2.20 (m, 1H) 2.52-3.04(m, 2H) 3.92 (m, 1H) 4.38-4.49 (m, 3H) 5.18 (m, 1H) 5.36-5.64 (m, 2H)6,22 (m, 1H) 8.12 (s, 1H)

EXAMPLE 372′,3′-Dideoxy-3′-fluoro-5′-O-[2,3-bis-(L-valyloxy)propanoyl]guanosine

a)2′,3′-Dideoxy-3′-fluoro-5′-O-[2,3-bis-(N-CBZ-L-valyloxy)propanoyl]guanosine(MSS-138)

A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (2.15 g, 8 mmole),2,3-bis-(N-CBZ-L-valyloxy)-propanoic acid (6.2 g, 10.8 mmole), DMAP (244mg, 2 mmole) and HOBT (1.46 g, 10.8 mmole) was coevaporated two timeswith DMF and reduced to about 120 ml. DCC (2.48 g, 12 mmole) was addedand the mixture was stirred for two days at room temperature. Themixture was filtered and the solution was evaporated under reducedpressure. 150 ml ethyl acetate was added and the organic phase waswashed twice with 5% acetic acid, with 5% sodium hydrogen carbonate andwith water. The organic phase was dried with sodium sulfate andevaporated under reduced pressure. The product was isolated by silicagel column chromatography. Yield: 2,25 g=35%

¹H-NMR (DMSO d-6) 0.88 (m, 12H) 2,12 (m, 2H) 2,50-3.00 (m, 2H) 3.88-4.14(m, 2H) 4.22-4.62 (m, 6H) 5.04 (s, 4H) 5.30-5.61 (m, 2H) 6.16 (m, 1H)6.50 (s, 2H) 7.32 (m, 10H) 7.70 (m, 2H) 7.92 (s, 1H)

b) 2′,3′-Dideoxy-3′-fluoro-5′-O-[2,3-bis-(L-valyloxy)propanoyl]guanosine

A solution of2′,3′-dideoxy-3′fluoro-5′-O-[2,3-bis-N-CBZ-L-valyloxy)propanoyl]guanosine(0.41 g, 0.5 mmole) in ethyl acetate (40 ml) and acetic acid (20 ml) washydrogenated with palladium black (200 mg) at 30 psi for two hours atroom temperature. The catalyst was filtered and washed with ethylacetate and acetic acid. The solution was evaporated under reducedpressure and the product was dried in vacuo to give the dihydrochloridesalt. Yield: 0.3 g=95%

¹H-NMR (DMSO d-6 and D₂O) 0.94 (m, 12H) 2.18(m, 2H) 2.52-3.00 (m, 214)3.88-4.09 (m, 2H) 4.36-4.72 (m, 6H) 5.42-5.72.

EXAMPLE 38 N1,N6-bis{(1S,2R)-1-[2-(4-(L-valyloxy)-butanoyloxy)]-indanyl}-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxyhexanediamide

a)N1,N6-bis{(1S,2R)-1-[2-(4-(N-Boc-L-valyloxy)-butanoyloxy)]-indanyl}-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxyhexanediamide

ToN1,N6-bis[(1S,2R)-1-(2-hydroxy)-indanyl]-(2R,3R,4R,5R)-2,5-di-(benzyloxy)-3,4-dihydroxyhexanediamidefrom WO 98/45330 (326 mg, 0.5 mmole) and 4-(N-Boc-L-valyloxy)butyricacid (295 mg, 1 mmole) in dichloromethane (3 ml) were added4-dimethylaminopyridine (12 mg, 0.1 mmole). The solution was cooled to−10° C. and DCC (206 mg, 1 mmole) in dichloromethane (2 ml) was addeddropwise over 2 hr. The reaction mixture was slowly warmed to roomtemperature, and kept for 18 hr. It was then filtered through Celite andpoured into sodium bicarbonate aqueous solution. The organic phase wasdried and the product was isolated with silica gel columnchromatography. 103 mg.

¹H-NMR (CDCl₃): 7.23 (m, 18H) 5.58 (m, 4H) 5.16 (d, 2H) 4.70-3.80 (m,12H) 3.08 (dd, 4H) 2.20 (m, 4H), 1.80 (m, 4H) 1.35 (m, 18H) 0.78 (dd,12H)

b)N1,N6-bis{(1S,2R)-1-[2-(4(L-valyloxy)-butanoyloxy)]-indanyl}-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxyhexanediamide

N1,N6-bis{(1S,2R)-1-[2-(4-(N-Boc-L-valyloxy)-butanoyloxy)]-indanyl}-(2R,3R,4R,5R)-2,5-di(benzyloxy)-3,4-dihydroxyhexanediamide (90 mg) was treatedwith trifluoroacetic acid (6 ml) at 0° C. for 2 hr. The solution wasdried and coevaporated with toluene and methanol successively, givingthe titled product in quantitative yield.

¹H-NMR (DMSO-d6+D₂O): 7.22 (m, 18H) 5.61 (m, 4H) 4.60-3.65 (m, 12H),3.12 (dd, 4 H) 2.15 (m, 4H) 1.80 (m, 4H) 0.90 (m, 12 H).

EXAMPLE 39

N1-{(1S,2R)-2-4-(L-valyloxy)butanoyloxy]-2,3-dihydro-1H-1-indenyl}-N6-[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di[4-(2-thiazolyl)benzyloxy]-3-hydroxy-4-[4-(L-valyloxy)butanoyloxy]hexanediamidebis-trifluoroacetate.

a)N1-[(1S,2R)-2-Hydroxy-2,3-dihydro-1H-1-indenyl]-N6-[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di[4-(2-thiazolyl)benzyloxy]-3,4-dihydroxyhexanediamide.

A mixture ofN1-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-1-indenyl]-N6-[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-bromobenzyloxy)-3,4-dihydroxyhexanediamide,prepared analagously to Example 11 of WO98/45330 using 4-bromobenzyl(130 mg, 0.164 mmol), tributyl-2-thiazolyltin (554 mg, 1.47 mmol),PdCl₂(PPh₃)₂ (120 mg, 0.5 M suspension in DMF), and dry DMF (3 ml) wastwice degassed and flushed with argon and then stirred at 90° C./16 h,evaporated to near dryness, washed with a little ether and purified bysilica gel column chromatography (chloroform-methanol 20:1) to yield95.5 mg (73%) of off-white solid.

¹³C NMR (CDCl₃; 62.9 MHz) δ 17.2, 19.4, 26.0, 29.5, 39.3, 57.6, 58.2,71.8, 72.2, 72.4, 81.0, 81.4, 118,8, 124.0, 125.3, 127.0, 127.1, 128.2,128.3, 128.4, 133.2, 138.5, 139.9, 140.6, 143.5, 167.5, 171.0, 171.3.

b)N1-{(1S,2R)-2-[4-(N-Boc-L-valyloxy)butanoyloxy]-2,3-dihydro-1H-1-indenyl}-N6-[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di[4-(2-thiazolyl)benzyloxyl-3-hydroxy-4-[4-(N-Boc-L-valyloxy)butanoyloxy]hexanediamide.

To obtain the di-acylated derivative, a solution of the intermediate ofstep a) (49.5 mg, 0.062 mmol), 4-(L-valyloxy)butyric acid (100 mg, 0.33mmol), dicyclohexylcarbodiimide (50 mg, 0.24 mmol), and4-(N,N-dimethylamino)pyridine (10 mg, 0.082 mmol) in dichloromethane (1ml) was kept at room temperature overnight. The precipitateddicyclohexylurea was filtered off and the solution evaporated to smallvolume and then purified by silica gel column chromatography(chloroform-hexane-methanol 20:10:1) to yield the title compound as aglass (71 mg, 84%)

¹³C NMR (CDCl₃; 62.9 MHz) δ 17.2, 17.3, 18.9, 19.1, 23.8,25.0, 28.2,30.4, 31.0, 37.3, 58.0, 58.5, 63.8, 70.5, 71.0, 71.1, 71.6, 75.6, 79.4,80.0, 118.8, 123.7, 125.0, 126.5, 127.1, 128.2, 128.6, 128.8, 133.3,138.2, 139.0, 140.1, 143.5, 155.4, 168.5, 170.5, 171.5, 172.0.

c)N1-{(1S,2R)-2-[4-(L-valyloxy)butanoyloxy]-2,3-dihydro-1H-1-indenyl}-N6-[(1S)-2-methyl-1-(methylcarbamoyl)propyl]-(2R,3R,4R,5R)-2,5-di(4-(2-thiazolyl)benzyloxy]-3-hydroxy-4-[4-(L-valyloxy)butanoyloxy]hexanediamidebis-trifluoroacetate.

The intermediate of step b) (71 mg, 0.0518 mmol) was dissolved in 1 mlof neat trifluoroacetic acid with cooling and kept at room temperaturefor 1 h. The solution was evaporated to small volume, lyophilized withdioxane, then with water containing 10% of dioxane, to give 66.6 mg(92%) of the title compound as off-white, light powder.

¹³C NMR (CDCl₃; 62.9 MHz) δ 17.5, 18.0, 23.6, 30.0, 31.1, 58.5, 65.0,71.2, 71.6, 119.1, 123.2, 124.0, 126.8, 128.2, 128.5, 128.8, 133.4,137.9, 139.3, 143.5, 161.7, 168.8, 169.1, 171.3.

EXAMPLE 40

a) Synthesis of 3-bromo-2-hydroxy-1-(N-CBz-L-valyloxy)-propane

To a stirred solution of 3-bromo-1,2-propanediol (10.85 g, 70mmole),N-CBz-L-valine (10.05 g, 40 mmole) and DMAP (0.49 g, 4 mmol) in 250 mldichloromethane was added dropwise a solution of DCC (9.1 g, 44 mmol) in50 ml dichloromethane at about 10° C. The mixture was stirred for twodays at room temperature and then cooled to 5° C. The urethane wasfiltered and the solution was evaporated under reduced pressure. Theproduct was isolated by silica gel column chromatography. Yield: 8 g

¹H-NMR (CDCl₃) 0.93 (m, 6H) 1.24(m, 1H) 2.15 (m, 1H) 3.10 (m, 1H) 3.45(m, 2H) 4.10 (m, 1H) 4.27 (m, 2H) 5.11 (s, 2H) 7.31 (m, 5H)

b) Synthesis of 3-bromo-2-stearoyloxy-1-(N-CBz-L-valyloxy)-propane.

To a stirred solution of 3-bromo-2-hydroxy-1-(N-CBZ-L-valyloxy)-propane(7.9 g, 20 mmol) and pyridin (3.2 g, 40 mmol) in 250 ml dichloromethanewas added dropwise a solution of stearoyl chloride (9.1 g, 30 mmol) in50 ml dichloromethane between 10° C. and 15° C. The solution was stirredovernight at room temperature. 150 ml of 5% sodium hydrogen carbonatesolution was added and the mixture stirred for 30 minutes. The organicphase was separated and the water phase was extracted two times withdichloromethane. The combined organic phases were dried with sodiumsulfate and concentrated in vacuo. The product was isolated by silicagel column chromtography. Yield: 10.5 g

¹H-NMR (CDCl₃) 0.88 (m, 9H) 1.25 (m, 28H) 1.58 (m, 2H) 2.08 (m, 1H) 2.22(m, 2H) 3.42 (m, 2H) 4.25 (m, 3H) 5.08 (s, 2H) 5.20 (m, 2H) 7.35 (m, 5H)

EXAMPLE 41 1-chloroethyl ester of3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butyric acid

a) Preparation of1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-1,3-propandiol.

To a solution of 2-allyl-1,3-propandiol (4.6 g, 40 mmole) andN-benzyloxycarbonyl valine (5.02 g, 20 mmol) were addeddimethylaminopyridine (244 mg, 2 mmol), and DCC (4.5 g, 22 mmol). Aftertwo hr, the mixture was filtered through Celite and evaporated. Theproduct 1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-1,3-propandiol wasisolated. 5.01 g

¹H-NMR (CDCl₃): 7.36 (m, 5H), 5.78 (m, 1H), 5.26 (d, 1H), 5.11 (s, 2H),5.06 (d, 2H), 4.22 (m, 3H), 3.59 (m, 2H), 2.13 (m, 3H), 1.98 (m, 2 H),0.94 (dd, 6 H).

b) Preparation of1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-3-O-stearoyl-1,3-propandiol

To a solution of1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-1,3-propandiol (4.46 g, 12.7mmole), in dichloromethane (70 ml) and pyridine (6.1 ml, 76 mmol) in anice bath was added stearoyl chloride (7.8 g, 26 mmol). The reactionmixture was warmed up to room temperature and kept for one hr. It wasthen poured into aqueous sodium hydrogen carbonate solution and theorganic phase was dried and the product1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-3-O-stearoyl-1,3-propandiolwas purified by silica gel column chromatography. 6.7 g

¹H-NMR (CDCl₃): 7.34 (m, 5H, 5.77 (m, 1H), 5.30 (d, 1H), 5.11 (s, 2H),5.08 (d, 2H), 4.32 (m, 1H), 4.10 (m, 4 H), 2.29 (t, 2H), 2.13 (m, 4H),1.62 (m, 3 H), 1.25 (m, 28 H), 0.90 (m, 9 H).

c) Preparation of3-(N-benzyloxycarbonyl-L-valyloxy)-4-stearoyloxy-butyric acid.

Potassium permanganate (756 mg, 4.8 mmole) was dissolved in water (7.5ml). The solution was kept under strong stirring for 10 min. A solutionof product1-O-(N-benzyloxycarbonyl-L-valyl)-2-allylyl-3-0stearoyl-1,3-propandiol(1 g, 1.6 mmole) and tetrabutylammonium bromide (77 mg, 0.24 mmol) inbenzene (5 ml) was added. The slurry was stirred for 1.5 hr, anddichloromethane was added. A sodium bisulfite aqueous solution was addedto the slurry until the mixture discolored. The organic phase wasacidified with acetic acid and washed with water. After evaporation, theproduct 3-(N-benzyloxycarbonyl-L-valyloxy)-4-stearoyloxy-butyric acid(390 mg) was isolated by silica gel column chromatography.

¹H-NMR (CDCl₃): 7.33 (m, 5H), 5.38 (d, 1H), 5.11 (s, 2H), 4.14 (m, 5 H);2.60 (m, 1H), 2.45 (m, 2 H), 2.29 (t, 2 H), 2.18 (m, 1 H), 1.58 (m, 2H),1.25 (m, 28 H), 0.90 (m, 9 H).

d) Preparation of3-(N-benzyloxycarbonyl-L-valyloxy)-4-stearoyloxy-butyroyl chloride.

3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butyric acid(1.26 g, 2 mmol), was treated with thionyl chloride (50 ml) at 35° C.for 3 hr, evaporated and coevaporated to give the product3-(N-benzyloxycarbonyl-L-valyloxy)4-stearoyloxy-butyroyl chloride (1.3g).

¹H-NMR (CDCl₃): 7.37 (m, 5), 5.30 (d, 1 H), 4.20 (m, 5H), 3.05 (m, 2H),2.70 (m, 1H), 2.35 (t, 2H), 2.15 (m, 1H), 1.70 (m, 4H), 1.25 (m, 28H),0.91 (m, 9H).

f) Preparation of 1-chloroethyl ester of3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butyric acid

To a mixture of3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butyroyl chloride(650 mg, 1 mmol) and acetaldehyde (0.062 ml, 1.1 mmol) was added 1 Mzinc chloride (0.02 ml, 0.02 mmol). After 2 hr, the reaction mixture wasloaded on a silica gel column and the titled product was isolated. 470mg.

¹H-NMR (CDCl₃): 7.34 (m, 5H), 6.53 (q, 1H), 5.38 (d, 1H), 5.10 (s, 2 H),4.16 (m, 5H), 2.60 (m, 1H), 2.48 (m, 5H), 2.15 (m, 1H), 1.68 (d, 3H),1.60 (m, 2H), 1.25 (m, 28H), 0.90 (m, 9H).

EXAMPLE 42 Application of a Trifunctional Linker to the Carboxy Functionof a Drug:

To a solution of cefotaxime sodium salt (0.338 g, 0.71 mmol) in DMF (5ml) was added the compound of Example 6 (0.5 g, o.63 mmol) in DMF (1ml). The mixture was stirred under nitrogen atmosphere at 40° C. untilTLC indicated consumption of the starting material. After 16 h, thesolvent was removed in vacuum and the residue dissolved in ethyl acetate(50 ml) and filtrated. The ethyl acetate was evaporated and the crudeproduct purified by chromatography [SiO₂, ethyl acetate/hexane (3:2)].Evaporation and drying in vacuum gave the above depicted compound (0.27g)

¹H-NMR (CDCl₃): δ 7.30 (m, 5H), 5.82 (m, 1H), 5.30 (m, 1H), 5.06 (m,2H), 4.6-4.02 (m, 5 H4.0 (s, 3H, ═N—OMe), 3.48 (m, 1H), 2.29 (t, 2H),2.15 (m, 1H), 2.05 m, 5H), 1.55 (m, 2H1.23 (m, 28H), 0.9 (m, 9H).

The CBz protecting group on the α-amine of the amino acid is removed byconventional deprotection treatments as described above.

EXAMPLE 43 Application of an Alternative Trifunctional Linker to aCarboxyl Function

A solution of the compound of Example 8 (220 mg, 0.28 mmol) and thesodium salt of Claforan (111 mg, 0.23 mmol in dry N,N-dimethylformamide(4.6 mL) was stirred at ambient temperature under nitrogen for 23 hr.After removal of solvent in vacuo, the residue was purified by flashcolumn chromatography on silica gel eluted successively with 1/1hexane-diethyl ether, 80/1 dichloromethane-methanol, and 40/1dichloromethane-methanol to give the above depicted compound as a lightyellow solid (161 mg).

¹H NMR (CDCl₃) d ppm 0.83-0.97 (m, 9H), 1.23 (s, 28H), 1.57 (m, 5H),2.07 (s, 3H), 2.13 (m, 1H), 2.28 (m, 2H), 3.50 (AB q, 2H), 4.02 (s, 3H),4.10-4.50 (m, 5H), 4.80-4.87 (m, 1H), 5,05-5.45 (m, 6H), 5.80-6.12 (m,1H), 6.65-7.70 (m, 2H), 7.33 (m, 5H).

The CBz protecting group on the α-amine of the amino acid is removed byconventional deprotection treatments as described above.

EXAMPLE 44 Application of an Alternative Trifunctional Linker to aCarboxyl Function

A mixture of claforan sodium salt (477,5 mg, 1,0 mmole) and3-bromo-2-stearoyloxy-1-(N-CBz-L-valyloxy)-propane (785.7 mg, 1.2 mmole)in 20 ml DMF was stirred for one week at room temperature. The solutionwas evaporated under reduced pressure and the product isolated by silicagel column chromatography. Yield: 310 mg

¹H-NMR (CDCl₃) 0.88 (m, 9H) 1.25 (m , 28H) 2,10 (m, 3H) 3.48 (m, 2H)4.04 (m, 3H) 4.26 (m, 5H) 5.06 (m, 4H).

The CBz protecting group on the α-amino group is removed withconventional deprotection conditions as described above.

EXAMPLE 45 Application of a Trifunctional Linker to an Hydroxyl BearingDrug

a) 6/18/20-O-mono-(6-(N-tritylvalyloxy)-5-(1-stearoyloxy methyl)hexanoyl) rifabutin

Dried rifabutin (343 mg, 0.42 mmol) and6-(N-tritylvalyloxy)-5-(1-stearoyloxy methyl) hexanoic acid (323 mg,0.42 mmol) were dissolved together in dry dichloromethane (3.5 ml). Thendimethylaminopyridine (6 mg, 0.05 mmol) and dicyclohexylcarbodiimide (93mg, 0.45 mmol) were added and the reaction mixture was stirred for 24 hat 20° C. The mixture was filtered and extracted with 5% aqueous sodiumbicarbonate and dichloromethane three times. The residue obtained byevaporation of the organic phase was chromatographed on silica gel andthe product was eluted with 0%→2% EtOH/dichloromethane. (Yield 316 mg).R_(f) (5% MeOH/CHCl₃): 0.75.

b) 6/18/20-O-mono-(6-(valyloxy)-5-(1-stearoyloxy methyl) hexanoyl)rifabutin. The product from step a) (316 mg, 0.2 mmol) was dissolved indioxane (2 ml) and then 80% acetic acid (20 ml) was added and thesolution was stirred for 5 min at 20° C. The solution was evaporated andcoevaporated with dioxane two times and toluene one time. The residuewas chromatographed on silica gel and the product was eluted with 0%→5%EtOH/dichloromethane. (Yield 230 mg). R_(f) (5% MeOH/CHCl₃): 0.50.

¹H-NMR (CHCl₃): 8.35 (br, 1H); 7.77 (s, 1H); 6.42 (d,d, 1H); 6.12 (m,2H); 5.91 (d,d, 1H); 5.12 (d, 1H); 5.07 (d,d, 1H); 4.94 (d, 1H);4.18-3.96(m, 4H); 3.46 (d, 1H); 3.31 (d,d, 1H); 3.05 (s, 3H); 2.98 (m,2H); 2.86 (d,d, 1H); 2.65 (m, 2H); 2.48 (q, 1H); 2.38-2.32 (m, 5H); 2.30(s, 3H); ); 2.13 (t, 2H); 2.05 (s, 3H); 2.01 (s, 3H); 2.00 (m, 2H);1.85-1.73 (m, 11H); 1.78 (s, 3H); 1.68-1.50 (m, 5H); 1.25 (m, 28H); 1.15(m, 2H); 1.05-0.85 (m, 21H); 0.47 (d, 3H); −0.18 (d, 3H).

EXAMPLE 46 Application of a Trifunctional Linker to an AlternativeHydroxy Drug

a) Preparation of dibenzyl ester of1,3-bis-(2-carboxychromon-5-yloxy)propan-2-ol.

1,3-bis(2-carboxychromon-5-yloxy)-propan-2-ol disodium salt (2.5 g, 5,2mmol), was suspended in DMF. To the suspension was added benzyl bromide(0.734 ml, 6.2 mmol) and the reaction was kept overnight under stirring.An additional portion of benzyl bromide (0.734 ml, 6.2 mmol) was added.After 24 hr, the reaction mixture was poured into sodium hydrogencarbonate aqueous solution and extracted dichloromethane. The organicphase was washed with water two times and evaporated to give thedibenzyl ester of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol (1.72 g).

¹H-NMR (CDCl₃): 7.58 (t, 2H), 7.40 (m, 10.9.), 7.16 (d, 2H), 6.98 (s,2H), 6.95 (d, 2H), 5.39 (s, 4H), 4.53 (m, 5H).

b) Preparation of the dibenzyl ester of2-[5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane.

To a solution of the dibenzyl ester of1,3-bis-(2-carboxychromon-5-yloxy)propan-2-ol (270 mg, 0.42 mmole),5-(N-Trityl-L-valyloxymethyl)-6-stearoyloxyhexanoic acid (323 mg, 0.42mmol) and dimethylaminopyridine (6 mg, 0.05 mmol) in dichloromethane wasadded DCC (92 mg, 0.45 mmol). After 3 days, the reaction mixture wasfiltered through Celite and the filtrate was washed with sodium hydrogencarbonate aqueous solution and dried. The product dibenzyl ester of2-[5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propanewas isolated from silica gel column chromatography. 250 mg.

¹H-NMR (CDCl₃): 7.60-7.20 (m, 27H), 7.18 (d, 2H), 6.93 (d, 2H), 6.88 (s,2H), 5.65 (m, 1H), 5.37 (s, 4H), 4.60 (m, 5H), 3.87 (m, 2H), 3.55 (m,1H), 3.22 (m, 2H), 2.38 (t, 2H), 2.24 (t, 2H), 2.20 (m, 1H), 1.70 (m,5H), 1.25 (m, 28H), 0.91 (m, 9H).

c) Preparation of2-[5-(L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane.

Dibenzyl ester of2-[5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane(238 mg, (0.17 mmol) was dissolved in ethyl acetate (1.5 ml). To thesolution was added 80% acetic acid (10 ml). After two hr, the solutionwas evaporated and purified by column chromatography to yield 197 mg of2-(5-(L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane.

¹H-NMR (CDCl₃): 7.57 (t, 2H), 7.44 (m, 10H), 7.08 (d, 2H), 6.95 (d, 2H),6.90 (s, 2H), 5.65 (m, 1H), 5.37 (s, 4H), 4.58 (m, 4H), 4.07 (m, 4H),3.40 (m, 2H), 2.43 (t, 2H), 2.27 (t, 2H), 2.10-1.40 (m, 8H), 1.24 (m,28H), 0.90 (m, 9H).

Preparation of2-[5-(L-valyloxymethyl)6-stearoyloxy-hexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane.

2-[5-(L-valyloxymethyl)-6-stearoyloxyhexanoyloxy]-1,3-bis-(2-carboxychromon-5-yloxy)propane(190 mg, 0.16 mmole) was dissolved in a mixed solvent of methanol (6ml), ethyl acetate (2 ml) and acetic acid (0.5 ml) and hydrogenated onpalladium black (30 mg) for 1 hr. After filtration, the solution wasdried and coevaporated with toluene giving 160 mg titled product.

¹H-NMR (DMSO δ-6): 7.77 (t, 2 H), 7.27 (d, 2 H), 7.12 (d, 2 H), 6.68 (s,2H), 5.60 (m, 1H), 4.60 (m, 4H), 4.05 (m, 5H), 2.50-2.10 (m, 6H),1.90-1.50 (m, 6H), 1.26 (m, 28H), 0.93 (m, 9H).

EXAMPLE 46 Iodomethyl3-[3-{1-(N-benzyloxycarbonyl)-L-valyloxy-3-stearoyloxypropyl-2-oxycarbonyl}propionyloxy]-2,2-dimethylpropionate

a) Preparation of(1-(N-benzyloxycarbonyl)-L-valyloxy)-3-stearoyloxypropyl-2-oxycarbonyl)Propionic acid

To a solution of(1-(N-benzyloxycarbonyl)-L-valyloxy)-3-stearoyloxypropan-2-ol (8.1 g,13.7 mmole) in N,N-dimethylformamide (135 ml) and pyridine (10 ml) wasadded succinic anhydride (4.1 g, 41.1 mmole) and the solution wasstirred for 72 hr at 60° C. The reaction was cooled to room temperatureand acetic amhydride (13 ml) was added and the solution was stirred overnight. The reaction was quenched by addition of aqueous sodium hydrogencarbonate solution (3 ml). After concentration on rotavapor, theresidual concentrated solution was poured into aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic phasewas evaporated and the residue silica gel column chromatographed (20,30, 50, 80% ethyl acetate in hexane). The appropriate fractions werepooled and evaporated in vacuo to give the title compound (6.8 g). R_(f)(5% MeOH/CHCl₂) 0.65.

¹H-NMR (CDCl₃): δ7.36 (m, 5H), 5.34 (m, 2H), 5.11 (s, 2H), 4.50-4.05 (m,5H), 2.64 (br s, 4H), 2.31 (t, 2H), 2.14 (m, 1H), 1.60 (m, 2H), 1.28 (brs, 28H), 0.95 (d, 3H), 0.86 (m, 6H).

b) Preparation of 4-methoxybenzyl3-[3-{1-(N-benzyloxycarbonyl)-L-valyloxy-3-stearoyloxypropyl-2-oxycarbonyl}propionyloxy]-2,2-dimethylpropionate

(1-(N-benzyloxycarbonyl)-L-valyloxy)-3-stearoyloxypropyl-2-oxycarbonyl)propionic acid

(5.8 g, 8.38 mmol), 4-methoxybenzyl 2-(hydroxymethyl)-2-methylpropionate (2.09 g, 8.80 mmole), 4-dimethylaminopyridine (153 mg) and1-hydroxybenzotriazole (1.13 g, 8.38 mmole) were mixed and dissolved inN,N-dimethylformamide (70 ml). Then dicyclohexyl-carbodiimide (2.07 g10.06 mmol) was added. After stirring for 4 days at room temperature thesuspension was filtered and the filtrate evaporated in vacuo. Theresidue was partitioned between 0.1M citric acid and dichloromethane.The organic phase was then extracted with aqueous saturated NaHCO₃ andevaporated in vacuo. The residue was silica gel column chromatographed(20, 30, 60, 100% ethyl acetate in hexane). The appropriate fractionswere pooled and evaporated in vacuo to give the title compound (5.73 g).

R_(f) (2% MeOH/CHCl₃) 0.80. ¹H-NMR (CDCl₃): δ7.32 (m, 5H), 7.26 (d, 2H),6.88 (d, 2H), 5.27 (m, 2H), 5.10 (s, 2H), 5.06 (s, 2H), 4.36-4.12 (m,5H), 4.10 (s, 21), 3.80 (s, 3H), 2.54 br s, 4H), 2.31 (t, 2H), 2.14 (m,1H), 1.60 (m, 2H), 1.26 (br s, 34H), 0.95 (d, 3H), 0.86 (m, 6H).

c) Preparation of3-[3-{1-(N-benzyloxycarbonyl])-L-valyloxy-3-stearoyloxypropyl-2-oxycarbonyl}propionyloxy]-2,2-dimethylpropionicacid 4-methoxybenzyl3-[3-{1-(N-benzyloxycarbonyl)-L-valyloxy-3-stearoyloxypropyl-2-oxycarbonyl}propionyloxy]-2,2-dimethylpropionatewas treated with trifluoroacetic aicd by the method described in ExampleII, step c. The title compound (4.08 g) was obtained after silica gelcolumn chromatography (20, 30, 50, 80% ethyl acetate in hexane). R_(f)(2% MeOH/CHCl₃) 0.55.

¹H-NMR (CDCl₃): 7.34 (s, 5H), 5.26 (m, 2H), 5.11 (s, 2H), 4.39-4.15 (m,5H), 4.10 (s, 2H), 2.61 (br s, 4H), 2.31 (t, 2H), 2.17 (m, 1H), 1.60 (m,2H), 1.26 (br s, 34H), 0.95 (d, 3H), 0.86 (m, 6H).

d) Preparation of chloromethyl3-[3-{1-(N-benzyloxycarbonyl)-L-valyloxy-3-stearoyloxypropyl-2-oxycarbonyl}propionyloxy]-2,2-dimethylpropionate

The propionic acid derivative of step c was esterified by the methoddescribed in Example A-I-1, step d. The title compound (3.3 g) wasobtained after silica gel column chromatography (20, 30% ethyl acetatein hexane). R_(f) (2% MeOH/CHCl₃) 0.85.

¹H-NMR (CDCl₃):): 7.34 (s, 5H), 5.71 (s, 2H), 5.27 (m, 2H), 5.11 (s,2H), 4.39-4.14 (m, 5H), 4.08 (s, 2H), 2.61 (s, 4H), 2.31 (t, 2H), 2.15(m, 1H), 1.60 (m, 2H), 1.26 (br s, 34H), 0.98 (d, 3H), 0.86 (m, 6H).

e) Preparation of iodomethyl3-[3-{1-(N-benzyloxycarbonyl)-L-valyloxy-3-stearoyloxypropyl-2-oxycarbonyl}propionyloxy]-2,2-dimethylpropionate

The chloromethyl ester of step d was converted to iodide by the methoddescribed in Example I, step e to give the title compound (1.96 g)practically pure. R_(f) (2% MeOH/CHCl₃) 0.85.

¹H-NMR (CDCl₃): 7.34 (s, 5), 5.91 (s, 2H), 5.29 (m, 2H), 5.11 (s, 2H),4.39-4.14 m, 5H), 4.08 (s, 2H), 2.61 (s, 4H), 2.31 (t, 2H), 2.15 (m,1H), 1.60 (m, 2H), 1.26 (br s, 34H), 0.98 (d, 3H), 0.86 (m, 6H).

EXAMPLE 47 Iodomethyl5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate

a) 4-Methoxybenzyl 2,2-dimethyl-4-pentenoate

To a solution of 2,2-dimethyl-4-pentenoic acid (11.5 g, 90 mmol) in DMF(250 mL) at room temperature, was added potassium tert-butoxide (11.1 g,99 mmol). The reaction mixture was stirred at 60° C. for 1 h.4-Methoxybenzylchloride (16.9 g, 108 mmol) was added and the reactionmixture was stirred at 60° C. for 4 h. The DMF was evaporated undervacuum, the residue was dissolved in ether (500 mL) and washed withwater (3×200 mL). The organic phase was dried with Na₂SO₄ and evaporatedto give 21.4 g of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate.

¹H-NMR (CDCl₃): 7.27 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 5.8-5.6(m, 1H), 5.1-4.9 (m, 2H), 5.03 (s, 2H), 3.80 (s, 3H), 2.27 (d, 2H), 1.17(s, 6H).

b) 4-Methoxybenzyl 4,5-dihydroxy-2,2-dimethylvalerate

To a mixture of 4-methoxybenzyl 2,2-dimethyl-4-pentenoate (22.5 g, 91mmol), NMO (36.7 g, 272 mmol) and tert-butanol (100 mL) in THF (400 mL)at 0° C., was added osmium tertoxide (230 mg, 0.9 mmol).). After 1 h at0° C., the temperature of the reaction mixture was allowed to assumeroom temperature and then the mixture was stirred for 4 h at roomtemperature. After evaporation, water (300 mL) was added and theresulting mixture was extracted with CH₂Cl₂ (5×300 mL). The combinedorganic layers were dried (Na₂SO₄) and concentrated under reducedpressure. The crude product was column chromatographed (silica gel,3→10% MeOH in CH₂Cl₂), to give 20.4 g of 4-methoxybenzyl4,5-dihydroxy-2,2-dimethylvalerate.

¹H-NMR (CDCl₃): 7.27 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 5.03 (s,2H), 3.8-3.7 (m, 1H), 3.79 (s, 3H), 3.51 (dd, 1H), 3.36 (dd, 1H), 3.04(br s, 1H), 2.74 (br s, 1H), 1.87 (dd, 1H), 1.46 (dd, 1H), 1.24 (s, 6H).

c) 4-Methoxybenzyl 5-(N-CBz-L-valyloxy)-4-hydroxy-2,2-dimethylvalerate.

To a mixture of DCC (14.8 g, 72 mmol), DMAP (0.88 g, 7.2 mmol) and4-methoxybenzyl 4,5-dihydroxy-2,2-dimethyl-valerate (20.3 g, 72 mmol) inCH₂Cl₂ (400 mL) at 0° C., was added dropwise a solution ofN-CBz-L-valine (16.2 g, 65 mmol) in CH₂Cl₂ (100 mL). After 1 h at 0° C.,the temperature of the reaction mixture was allowed to assume roomtemperature and then the mixture was stirred for 5 h at roomtemperature. The mixture was filtered through a glass filter and thesolvent was removed under reduced pressure. The crude product was columnchromatographed (silica gel, 2→5% MeOH in CH₂Cl₂), to give 22.4 g4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-hydroxy-2,2-dimethylvalerate.

¹H-NMR (CDCl₃): 7.35 (s, 5H), 7.28 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz,2H), 5.26 (d, 1H), 5.11 (s, 2H), 5.04 (s, 2H), 4.29 (dd, 1H), 4.1-3.9(m, 2H), 3.80 (s, 3H), 2.50 (br s, 1H), 2.3-2.1 (m, 1H), 2.0-1.8 (m,1H), 1.6-1.4 (m, 1H), 1.24 (s, 6H), 0.98 (d, 3H), 0.90 (d, 3H).

d) 4-Methoxybenzyl5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate

To a mixture of 4-methoxybenzyl5-(N-CBz-L-valyloxy)-4-hydroxy-2,2-dimethylvalerate (20.6 g, 40 mmol),Pyridine (31.6 g, 400 mmol) in CH₂Cl₂ (500 mL) at 0° C., was addeddropwise a solution of stearoyl chloride (18.2 g, 60 mmol) in CH₂Cl₂(100 mL). After 1 h at 0° C., the temperature of the reaction mixturewas allowed to assume room temperature and then the mixture was stirredfor 5 h at room temperature. The mixture was extracted with a 10%aqueous solution of NaHCO₂ (300 mL) and the aqueous phase was washedwith CH₂Cl₂ (200 mL). The combined organic layers were dried (Na₂SO₄)and concentrated under reduced pressure. The crude product was columnchromatographed (silica gel, 1→5% MeOH in CH₂Cl₂), to give 27.2 g of4-metoxybenzyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate.

¹H-NMR (CDCl₃): 7.37 (s, 5H), 7.28 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz,2H), 5.3-5.0 (m, 4H), 5.11 (s, 2H), 4.4-4.2 (m, 2H), 4.1-3.9 (m, 1H),3.80 (s, 3H), 2.2-2.0 (m, 4H), 1.8-1.5 (m, 3H), 1.3-1.1 (m, 34H),1.0-0.8 (m, 9H).

e) 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2dimethylvaleric acid

To a solution of 4-methoxybenzyl5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate (25.5 g, 33mmol) in CH₂Cl₂ (400 mL) at room temperature, was added trifluoroaceticacid (40 mL). After 1 h at room temperature, the reaction mixture wasconcentrated under reduced pressure. The crude product was columnchromatographed (silica gel, 3→5% MeOH in CH₂Cl₂), to give 19.8 g of5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvaleric acid.

¹H-NMR (CDCl₃): 7.37 (s, 5H), 5.3-5.1 (m, 2H), 5.11 (s, 2H), 4.4-4.2 (m,2H), 4.1-3.9 (m, 1H), 2.2-2.0 (m, 4H) 1.8-1.5 (m, 3H), 1.3-1.1 (m, 34H),1.0-0.8 (m, 9H).

f) chloromethyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate.

To a solution of 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalericacid (16.0 g, 24 mmol) in dioxane (500 mL), was added dropwise a 40%aqueous solution of tetrabutylammonium hydroxide (14.3 mL). Afterstirring for 5 min, the solution was evaporated to dryness throughco-evaporation with dioxane and toluene. The residue was dissolved indichloromethane (500 mL) and then chloroiodomethane (17.5 mL, 240 mmol)was added and the solution was stirred for 6 h at room temperature. Thesolution was concentrated under reduced pressure and the residue wasshaken with hexane/ethyl acetate (1:1 v/v, 400 mL). The yellowcrystalline solid was filtered off and the filtrate was washed withaqueous solution of sodium thiosulfate (0.1 M) and the filtered throughanhydrous sodium sulfate and evaporated to dryness. The residue wascolumn chromatographed (silica gel, 1% MeOH in CH₂Cl₂), to give 11.0 gof chloromethyl 5-(N-CBz-L-valyloxy)4-stearoyloxy-2,2-dimethylvalerate.

¹H-NMR (CDCl₃): 7.35 (s, 5H), 5.8-5.6 (m, 2H), 5.3-5.1 (m, 2H), 5.11 (s,2H), 4.4-4.2 (m, 2H), 4.1-3.9 (m, 1H), 2.3-2.1 (m, 4H), 1.8-1.5 (m, 3H),1.3-1.1 (m, 34H), 1.0-0.8 (m, 9H).

g) Iodomethyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate.

To a solution of chloromethyl5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate (7.8 g, 11 mmol)in acetonitrile (100 mL), was added sodium iodide (6.5 g, 44 mmol). Thesolution was stirred for 4 h at 60° C. The resulting suspension wasfiltered and the filtrate was evaporated. The residue was dissolved inCH₂Cl₂ and washed with aqueous sodium thiosulfate (0.1 M). The organicphase was dried (Na₄SO₄) and concentrated under reduced pressure. Thecrude product was column chromatographed (silica gel, 1% MeOH inCH₂Cl₂), to give 7.84 g of iodomethyl5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate

¹H-NMR (CDCl₃): 7.34 (s, 5H), 6.0-5.8 (m, 2H), 5.3-5.1 (m, 2H), 5.10 (s,2H), 4.4-4.2 (m, 2H), 4.1-3.9 (m, 1H), 2.3-2.0 (m, 4H), 1.8-1.5 (m, 3H)1.3-1.1 (m, 34H), 1.0-0.8 (m, 9H).

EXAMPLE A-1 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,tri(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,tri(2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionyl-oxymethyl)ester and 4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonicacid, di(2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionyloxymethyl)ester.

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid isprepared by the methodology in Kieczykowski et al, J Org Chem 1995, 60,8310-8312, and the 4-amino group CBz protected as shown in U.S. Pat. No.5,227,506. To a solution thereof (195 mg, 0.51 mmole) in dryN,N-dimethylformamide (2 ml), was added diisopropylethyl-amine (0.27 ml,1.53 mmole), followed by an injection of a solution of iodomethyl2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionate (626 mg,1.27 mmole) in N,N-dimethylformamide (2 ml). After stirring under argonfor 2,5 h at room temperature, the solution was concentrated onrotavapor and treated with ethyl acetate (10 ml). Crystals were filteredoff and the filtrate was extracted with brine containing a small amountof sodium thiosulfate. The organic phase was filtered through anhydroussodium sulfate and evaporated. The title compounds were isolated bysilica gel column chromatography (0-4, 7-8, 20-30% ethanol indichloromethane).

Triester (70 mg). R_(f) (10% MeOH/CHCl₃) 0.45. ¹H-NMR (CDCl₃): 7.30 (m,20H), 5.85-5.43 (m, 9H), 5.08 (m, 8H), 4.36-3.95 (m, 9H), 3.10 (m, 2H),2.15-1.75 (m, 7H), 1.19 (s, 18H), 0.86 (m, 18H). ³¹P-NMR (CDCl₃+1%CD₃OD) (H₃PO₄ reference): δ 23.8 (d), 11.8(d);

Diester (185 mg), R_(f)(10% MeOH/CHCl₃) 0.10 (at the center of oval spotfrom baseline). ¹H-NMR (CDCl₃+1% CD₃OD): 7.31 (m, 15H), 5.79-5.63 (m,4H), 5.08 (m, 6H), 4.35-4.10 (m, 6H), 3.10 (m, 2H), 2.18-1.70 (m, 6H),1.19 (m, 12H) 0.87 (m, 12H). ³¹P-NMR (CDCl₃+1% CD₃OD)(H₃PO₄ reference):δ 16.6 (s).

b) 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,tri(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester.

A solution of4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acidtri(2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionyloxymethyl)Ester (203 mg, 0.136 mmol) in methanol/ethyl acetate/acetic acid (2:1:1v/v/v) (8.7 ml) was hydrogenated over a Pd-black catalyst (93 mg) at 40psi of hydrogen for 16 h. The suspension was filtered through Celite ona fine pore sized glassinter and washed with methanol/ethyl acetate(2:1). The filtrate was evaporated to dryness in vacuo and the titlecompound as the tetra acetate was obtained as a white solid after a fewco-evaporations with dioxane and hexane.

³¹P-NMR (CDCl₃+5% CD₃OD)(H₃PO₄ reference): δ 23.1 (m), 11.1 (m).

EXAMPLE A-2 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester.

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionyloxymethyl)ester(130 mg, 0.112 mmol) was hydrogenated over Pd-black (48 mg) by themethod of Example A-1 b), to give the title compound as the triacetateas a white solid (90 mg).

³¹P-NMR (CDCl₃+5% CD₃OD)(H₃PO₄ reference): δ 16.2 (br, s).

EXAMPLE A-3 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-methyl-2-(L-valyloxy) propionyloxymethyl)ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-methyl-2-(N-benzyloxycarbonyl-L-valyoxy)propionyloxymethyl)ester.

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (306mg, 0.80 mmole) was esterified by the method described in Example A-1-a.After silica gel column chromatography (2-4, 6-12, 15-20% ethanol indichloromethane), the pure fractions containing the title compound werepooled together and evaporated. The residue was then dissolved in ethylacetate and the solution extracted twice with aqueous saturated sodiumbicarbonate and then twice with 5% aqueous EDTA-disodium salt. (116 mgof title compound). R_(f) (20% MeOH/CHCl₃) 0.20 (at the center of ovalspot from baseline).

¹H-NMR (CDCl₃+1% CD₃OD): 7.28 (m, 15H), 5.60 (m, 4H), 5.05 (m, 6H), 4.13(m, 2H), 3.09 (m, 2H), 2.19-1.72 (m, 6H), 1.49 (m, 12H), 0.89 (m, 12H).³¹P-NMR (CDCl₃+1% CD₃OD)(H₃PO₄ reference): δ 15.3 (s).

b) 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-methyl-2-(L-valyloxy)propionyloxymethyl)ester.

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-methyl-2-(N-benzyloxycarbonyl-L-valyloxy)propionyloxymethyl)ester(116 mg, 0.107 mmol) was hydrogenated over Pd-black (46 mg) by themethod of Example A-1-b, to give the title compound as the triacetate asa white solid (71 mg).

³¹P-NMR (CDCl₃+5% CD₃OD)(H₃PO₄ reference): δ 14.9 (s).

EXAMPLE A-4 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butryloxymethyl)ester.

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (383mg, 1 mmole) was esterified by the method described in Example A-3-a toyield 184 mg of title compound. R_(f) (20% MeOH/CHCl₃) 0,20 (at thecenter of oval spot from baseline).

¹H-NMR (CDCl₃+1% CD₃OD): 7.27 (m, 15H), 5.62 (m, 4H), 5.15-4.72 (m, 8H),4.32 (m, 2H), 3.08 (m, 2H), 2.16-1.73 (m, 6H), 0.88 (m, 24H). ³¹P-NMR(CDCl₃+1% CD₃OD)(H₃PO₄ reference): δ 15.5 (s).

b) 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-(L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester.

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyryloxymethyl)ester(184 mg, 0.166 mmol) was hydrogenated over Pd-black (71 mg) by themethod of Example A-1-b, to give the title compound as the triacetate asa white solid (95 mg).

³¹P-NMR (CDCl₃+5% CD₃OD)(H₃PO₄ reference): δ 14.6 (s).

EXAMPLE A-5 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, mono(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl) ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,tribenzyl mono (2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionyloxymethyl) ester.

To a solution of4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid(1.54 g, 4 mmole) in dry N,N-dimethylformamide (24 ml), heated at 50°C., was added diisopropylethylamine (2.78 ml, 16 mmole), followed bydropwise addition of benzylbromide (1.9 ml, 16 mmole). After stirringunder argon for 4 h, the solution was concentrated on rotavapor andtreated with ethyl acetate (20 ml). Crystals were filtered off and thefiltrate was extracted with brine. The organic phase was filteredthrough anhydrous sodium sulfate and evaporated. The4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,tribenzylester was isolated by silica gel column chromatography (2-4,7-10, 15-20% ethanol in dichloromethane). The pure fractions containingthe pure triester were pooled together and evaporated. The residue wasthen dissolved in ethyl acetate and the solution extracted three timeswith 2M aqueous solution of citric acid. Triester (990 mg); R_(f) (20%MeOH/CHCl₃) 0.15 (at the center of oval spot from baseline);

³¹P-NMR (CDCl₃) (H₃PO₄ reference): δ 20.4(d), 13.3 (d); ¹H-NMR (CDCl₃):7.35-7.10 (m, 20H), 5.20-4,91 (m, 8H), 4.60 (br, 1H), 3.00 (m, 2H),2.12-1.75 (m, 4H).

b) Dried tribenzyl ester (395 mg) was dissolved in dryN,N-dimethylformamide (3 ml), followed by addition ofdiisopropylethylamine (99 ml) and a solution of iodomethyl2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionate (737 mg) inN,N-dimethylformamide (1 ml). After stirring under argon for 4 h at 30°C., the solution was concentrated to dryness on rotavapor and treatedwith ethyl acetate (10 ml). Crystals were filtered off and the filtratewas extracted with brine brine containing a small amount of sodiumthiosulfate. The organic phase was filtered through anhydrous sodiumsulfate and evaporated. The title compound (84 mg) was isolated bysilica gel column chromatography (1, 2, 3% ethanol in dichloromethane).R_(f) (2% MeOH/CHCl₃) 0.60;

³¹P-NMR (CDCl₃) (H₃PO₄ reference): δ 16.4(m). ¹H-NMR (CDCl₃): 7.28 (m,25H), 5.22 (d, 1H), 5.62-5.53 (m, 3H), 5.07, 5.04 (2xs, 10H), 4.93 (br,1H), 4.27 (d,d, 1H), 4.15 (d,d, 2H), 3.11 (m, 2H), 2.13-1.77 (m, 5H),1.17 (s, 6H), 0.92 (d, 3H), 0.83 (d, 3H).

c) 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, mono(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl)ester.

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acidtribenzyl mono(2-methyl-2-(N-benzyloxycarbonyl-L-valyloxymethyl)propionyloxymethyl)ester (84 mg, 0.083 mmol) was hydrogenated over Pd-black (60 mg) by themethod of Example A-1-b, to give the title compound as a white solid (35mg).

³¹P-NMR (CDCl₃+5% CD₃OD)(H₃PO₄ reference):δ 14.5 (m).

EXAMPLE A-6 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-(-L-valyloxy)-2-phenyl-DL-acetyloxymethyl) ester

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (192mg, 0.5 mmole) was esterified by the method described in Example A-3-ato yield 72 mg of the title compound as the tri-N-CBz protected form,ready for deprotection. R_(f) (20% MeOH/CHCl₃) 0.20 (at the center ofoval spot from baseline).

¹H-NMR (CDCl₃+1% CD₃OD): 7.44-7.10 (m, 25H), 5.94 (m, 2H), 5.59 (m, 2H),5.18-4.85 (m, 6H), 4.36 (m, 2H), 3.00 (m, 2H), 2.12-1.63 (m, 6H), 0.95(m, 12H). ³¹P-NMR (CDCl₃+1% CD₃OD)(H₃PO₄ reference): δ 15.5 (s).

EXAMPLE A-7 4-amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi((1,3-di-valyloxy)propyl-2-oxycarbonyloxy methyl)ester.

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (141mg, 0.37 mmole) was esterified by the method described in Example A-1-ato yield 90 mg of title compound as the tri CBz protected form, readyfor deprotection. R_(f) (10% MeOH/CHCl₃) 0.20 (at the center of ovalspot from baseline). (153 mg of mixture of the diester and triester).

¹H-NMR (CDCl₃+1% CD₃OD) of title compound: 7.29 (m, 25H), 5.65 (m, 4H),5.14-4.85 (m, 12H), 4.45-4.05 (m, 12H), 3.11 (m, 2H), 2.14-1.76 (m, 5H),0.87 (m, 24H). ³¹P-NMR (CDCl₃+1% CD₃OD)(H₃PO₄ reference): δ 16.7 (s).

EXAMPLE A-8 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-L-valyloxy)-DL-propionyloxymethyl) ester

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (158mg, 0.41 mmole) was esterfied by the method described in Example A-3-ato yield 110 mg of the title compound as the tri N-Boc protected from,ready for deprotection. R_(f) (20% MeOH/CHCl₃) 0.15 (at the center ofoval spot from baseline).

¹H-NMR (CDCl₃+1% CD₃OD): 7.29 (m, 15H), 5.65 (m, 4H), 5.15-4.95 (m, 8H),4.33 (m, 2H), 3.09 (m, 2H), 2.22-1.74 (m, 6H), 1.52 (m, 6H), 0.92 (m,12H). ³¹P-NMR (CDCl₃+1% CD₃OD)(H₃PO₄ reference): δ 16.8 (s).

EXAMPLE A-9 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl) ester

a) 4-Benzyloxy carbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-(5-(N-CBz-L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester

To a solution of4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (575mg, 1.50 mmol) in DMF (10 mL), was added diisopropylamine (0.78 mL, 4.5mmol), followed by an injection of a solution of give iodomethyl5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate (1.95 g, 3.75 mmol) in DMF (5mL). After stirring under argon for 1.5 h at room temperature, thesolution was concentrated on rotavapor and treated with ethyl acetate(100 mL). Crystals were filtered off and the filtrate was extracted withbrine containing a small amount of sodium thiosulfate. The organic phasewas filtered through anhydrous sodium sulfate and evaporated. Aftersilica gel column (silica gel, 4→20% MeOH in CH₂Cl₂), the pure fractionscontaining the title compound were combined and evaporated. The residuewas then dissolved in ethyl acetate and the solution extracted twicewith aqueous saturated sodium bicarbonate and then twice with 5% aqueousEDTA-disodium salt. The ethyl acetate phase was evaporated, to give 171mg of 4-benzyloxy carbonylamino-1-hydroxybutylidene-1,1-bisphosphonicacid di-(5-(N-CBz-L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester.

¹H-NMR (CDCl₃): 7.30 (br s, 15H), 5.85-5.25 (m, 4H), 5.20-4.95 (m, 6H),4.30-3.95 (m, 6H), 3.18-3.00 (m, 2H), 2.20-1.75 (m, 6H), 1.7-1.4 (m,8H), 1.3-1.0 (s, 12H), 1.0-0.8 (m, 12H). ³¹P-NMR (CDCl₃)(H₃PO₄reference): 16.0 (s).

b) 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester

A solution of 4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-(5-(N-CBz-L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester (171 mg,0.147 mmol) in methanol/ethyl acetate/acetic acid (2:1:1 v/v/v) (20 mL)was hydrogenated over a Pd-black catalyst (30 mg) at 40 psi of hydrogenfor 6 h. The suspension was filtered through celite and the filtrate wasevaporated to dryness under reduced pressure, to give 95 mg of4-amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-(5-(L-valyloxy)-2,2-dimethylvaleryloxymethyl)ester was obtained as awhite solid.

1H-NMR (CDCl₃): 5.75-5.30 (m, 4H), 5.20-4.95 (m, 6H), 4.20-3.80 (m, 6H),3.00-2.80 (m, 2H), 2.20-1.40 (m, 14H), 1.3-1.0 (m, 12H), 1.0-0.8 (m,12H). ³¹P-NMR (CDCl₃+CD₃OD)(H₃PO₄ reference): δ 17.3 (br s)

EXAMPLE A-10 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-((2-(L-valyloxy-ethoxycarbonyloxy)methyl)ester

a) 4-benzyloxy carbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-((2-(N-CBz-L-valyloxy)-ethoxycarbonyloxy)methyl)ester

To a solution of4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (550mg, 1.44 mmol) in DMF (10 mL), was added diisopropylamine (0.75 mL, 4.32mmol), followed by an injection of a solution of2-(N-CBz-L-valyloxy)-ethyl iodomethyl carbonate (1.40 g, 3.60 mmol) inDMF (5 mL). After stirring under argon for 1.5 h at room temperature,the solution was concentrated on rotavapor and treated with ethylacetate (100 mL). Crystals were filtered off and the filtrate wasextracted with brine containing a small amount of sodium thiosulfate.The organic phase was filtered through anhydrous sodium sulfate andevaporated. After silica gel column (silica gel, 4→20% MeOH in CH₂Cl₂),the pure fractions containing the title compound were combined andevaporated. The residue was then dissolved in ethyl acetate and thesolution extracted twice with aqueous saturated sodium bicarbonate andthen twice with 5% aqueous EDTA-disodium salt. The ethyl acetate phasewas evaporated, to give 160 mg of 4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-((2-(N-CBz-L-valyloxy)-ethoxycarbonyloxy)methyl)ester.

¹H-NMR (CDCl₃): 7.29 (br s, 15H), 5.90-5.30 (m, 4H), 5.15-4.90 (m, 6H),4.50-4.00 (m, 10H), 3.18-3.00 (m, 2H), 2.20-1.50 (m, 6H), 1.05-0.80 (m,12H).

³¹P-NMR (CDCl₃)(H₃PO₄ reference): 16.5 (s).

b) 4Amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-((2-(L-valyloxy)-ethoxycarbonyloxy) methyl)ester

A solution of 4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-((2-(N-CBz-L-valyloxy)-ethoxycarbonyloxy)methyl)ester (160 mg, 0.147mmol) in methanol/ethyl acetate/acetic acid (2:1:1 v/v/v) (20 mL) washydrogenated over a Pd-black catalyst (30 mg) at 40 psi of hydrogen for7 h. The suspension was filtered through celite and the filtrate wasevaporated to dryness under reduced pressure, to give 100 mg of4-amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-((2-(L-valyloxy)-ethoxycarbonyloxy)methyl)ester was obtained as awhite solid.

¹H-NMR (CDCl₃): 5.80-5.40 (m, 4H), 4.70-4.05 (m, 10H), 4.4-4.2 (m, 4H),3.00-2.80 (m, 2H), 2.20-1.50 (m, 6H), 1.05-0.80 (m, 12H).

³¹P-NMR (CDCl₃+CD₃OD)(H₃PO₄ reference): δ 17.5 (br s).

EXAMPLE A-11 4-Amino-1-hydroxybutyliden-1,1-biphosphonic acidbis[2,2-dimethyl-3-(D-valyloxy)-propionyloxymethyl]ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acidbis[2,2-dimethyl-3-(N-CBZ-D-valyloxy)-propionyloxymethyl]ester

To a solution of4-benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acid (382mg, 1 mmole) and diisopropylethyl (0.43 ml, 2.5 mmole) in DMF (3 ml) at−40° C. was added 2,2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acidiodomethyl ester (1.23 g, 2.5 mmole) in DMF (4 ml). The reaction waskept at 0° C. for 2.5 hr and then at 4° C. for 18 hr. The reactionmixture was evaporated in vacuo and ethyl acetate (20 ml) was added. Theprecipitate was filtered off and the organic phase was washed withsodium bicarbonate aqueous solution and dried. The product was isolatedwith silica gel column chromatography. 125 mg.

¹H-NMR (CDCl₃): 7.31 (m, 15 H) 5.71 (m, 4 H) 5.58 (d, 2 H) 5.12 (s, 4H)5.05 (s, 2H) 4.30 (dd, 2H) 4.12 (m, 4 H) 3.18 (m, 2H) 2.05 (m, 6 H) 0.92(dd, 12 H). ³¹P-NMR (CDCl₃): 15.1

b) 4-Amino-1-hydroxybutyliden-1,1-bisphosphonic acidbis[2,2-dimethyl-3-(D-valyloxy)-propionyloxymethyl]ester:

4-Benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acidbis[2,2-dimethyl-3-(N-CBZ-D-valyloxy)-propionyloxymethyl]ester (130 mg)was dissolved in a mixed solvent of EtOAc/MeOH/AcOH (6 ml/3 ml/1.5 ml).To the solution was added palladium black (60 mg). The reaction was keptunder hydrogen atmosphere (40 psi) until sampling showed the completedeprotection of the benzyloxycarbonyl groups. The reaction mixture wasfiltered, and then dried and coevaporated with toluene and methanol,giving the titled product. 102 mg.

³¹P-NMR (CDCl₃+CD₃OD ):14.1

EXAMPLE A-12 4-Amino-1-hydroxybutyliden-1,1-bisphosphonic acidbis[4-(N-CBz-L-valyloxy)-butanoyloxymethyl]ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acidbis[4-(N-CBz-L-valyloxy)-butanoyloxymethyl]ester.

4-Benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acid (573mg, 1.5 mmole) was dissolved in dioxane (10 ml). To the solution wasadded tetrabutylammonium hydroxide (40%, 2.43 ml, 3.75 mmole). Thesolution was evaporated and coevaporated with DMF several times. Theresidue was dissolved in DMF (5 ml). To the solution was added4-(N-CBz-L-valyloxy) butyric acid iodomethyl ester (1.79 g, 3.75 mmole)in DMF (5 ml) portionwise in one hour. The reaction was kept at roomtemperature for 3 hr and then evaporated in vacuo. Later, ethyl acetate(20 ml) was added. The precipitate was filtered off and the organicphase was washed with sodium bicarbonate aqueous solution and dried. Theproduct was isolated with silica gel column chromatography. 135 mg.

¹H-NMR (CDCl₃):7.25 (m, 15 H) 5.60 (m, 6 H) 5.05 (m, 8H) 4.30-3.90 (m, 6H) 3.10 (m, 2 H) 2.50-1.80 (m, 14 H) 0.35 (m, 12H). ³¹P-NMR (CDCl₃):13.7.

b) 4-amino-1-hydroxybutyliden-1,1-bisphosphonic acid bis4-(L-valyloxy)-butanoyloxymethyl]ester

4-Benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acidbis[4-(N-CBz-L-valyloxy)-butanoyloxymethyl]ester (100 mg) was dissolvedin a mixed solvent of EtOAc/MeOH/AcOH (6 ml/3 ml/1.5 ml). To thesolution was added palladium black (80 mg). The reaction was kept underhydrogen atmosphere (40 psi) until sampling showed the completedeprotection of the benzyloxycarbonyl groups. The reaction mixture wasfiltered, and then dried and coevaporated with toluene and methanol,giving the titled product. 70 mg.

³¹P-NMR (CD₃OD): 17.7

EXAMPLE A-13 4-amino-1-hydroxybutyliden-1,1-bisphosphonic acid,di-(3-(L-valyloxy)benzoyloxymethyl)ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acid,di-(3-(N-benzyloxycarbonyl-L-valyloxy)benzoyloxymethyl)ester.

To a solution of4-benzyloxycarbonylamino-1-hydroxybutyliden-1,1-biphosphonic acid (0.59g, 1.5 mmole) and diisopropylethyl-amine (0.64 g, 5 mmole) inN,N-dimethylformamide (40 ml) was added dropwise a solution ofiodomethyl-3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate (2.2 g, 4.3mmole) in N,N-dimethylformamide (5 ml). The mixture was stirred 2 hoursat room temperature under argon. The mixture was evaporated underreduced pressure. Ethyl acetate (50 ml) was added and the mixture wasfiltered after 2 hours. The organic phase was washed twice with 5%sodium hydrogencarbonate solution and dried with sodium sulfate. Theproduct was isolated by silica gel column chromatography.

Yield: 0.23 g=15% ¹H-NMR (CDCl₃+5% CD₃OD) 0.89 (m, 12H) 1.58-2.28 (m,6H) 2.92 (m, 2H) 4.26 (m, 2H) 5.00 (m, 6H) 5.46-6.02 (m, 4H) 6.78-7.86(8m, 23H) ³¹P-NMR (CDCl₃+5% CD₃OD) 16.5 (s)

b) 4-amino-1-hydroxybutyliden-1,1-bisphosphonic acid,di-(3-(L-valyloxy)benzoyloxymethyl) ester.

Deprotection of tho CBz groups of4-benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acid,di-(3-(N-benzyloxycarbonyl-L-valyloxy)benzoyloxymethyl) ester using mildconditions as specified in Greene, “Protecting Groups in OrganicSynthesis, (John Wiley & Sons, New York, 1981) yields the titlecompound.

EXAMPLE A-14 4-Amino-1-hydroxybutyliden-1,1-bisphosphonic acid,di-(3-(L-valyloxy)-propionyloxymethyl) ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acid,di-(3-(N-benzyloxycarbonyl-L-valyloxy)-propionyloxymethyl)ester.

To a solution of4-benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acid (0.88g, 2,5 mmole) and diisopropylethyl-amine (0.78 g, 6 mmole) inN,N-dimethylformamide (40 ml) was added dropwise a solution ofiodomethyl-3-(N-benzyloxycarbonyl-L-valyloxy)-propionate (2.3 g, 4.95mmole) in N,N-dimethylformamide (5 ml). The mixture was stirred 2 hoursat room temperature under argon and evaporated under reduced pressure.Ethyl acetate (50 ml) was added and the mixture was filtered after 2hours. The organic phase was washed twice with 5% sodiumhydrogencarbonate solution and dried with sodium sulfate. The productwas isolated by silica gel column chromatography. Yield: 0.19 g=8%

¹H-NMR (CDCl₃+5% CD₃OD) 0.89 (m, 12H) 1.62-2.16 (m, 61i) 2.60 (m, 4H)3.08 (m, 2H) 4.12 (m, 2H) 4.30 (m, 4H) 5.02 (m, 6H) 5.42-5.64 (m, 4H)7.24 (m, 15H) ³¹P-NMR (CDCl₃+5% CD₃OD) 16,9 (s)

b) 4-Amino-1-hydroxybutyliden-1,1-bisphosphonic acid,di-(3-(L-valyloxy)-propionyloxymethyl) ester

Deprotection of the CBz groups of4-benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acid,di-(3-(N-benzyloxycarbonyl-L-valyloxy)-propionyloxymethyl) ester usingmild conditions as specified in Greene, “Protecting Groups in OrganicSynthesis, (John Wiley & Sons, New York, 1981) yields the titlecompound.

EXAMPLE C-1 1-[(1,3-bis(L-valyloxy)-2-propoxy)carbonyloxy]ethyl(7R)-3-acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylate

a)1-[(1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propoxy)carbonyloxy]ethyl(7R)-3-acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylate

A solution of 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl1-iodoethyl carbonate (0.156 mmol) and cefotaxime sodium (67.8 mg, 0.142mmol) in 3.2 mL dry N,N′-dimethylformamide was stirred under argon for22 h. The reaction mixture was concentrated and subjected to columnchromatography (silica, 2/1 petroleum ether-ethyl acetate, and then 20/1CH₂Cl₂-methanol) to yield an oil enriched in the desired product. Theoil was dissolved in 10 mL ethyl acetate, washed with water, dried, andconcentrated. A second chromatography (silica, 40/1 CH₂Cl₂-methanol)gave the title compound (59.7 mg) as cream-colored solids.

¹H NMR (250 MHz, CDCl₃) δ 0.84-0.89 (m, 6H), 0.91-0.96 (m, 6H), 1.43 (s,18H), 1.57 (d, 3H, J=5.5 Hz), 2.07 and 2.08 (2s, 3H total), 2.04-2.18(br, 2H) 3.40-3.64 (m, 2H), 4.03 and 4.04 (2s, 3H total), 4.18-4.51 (m,6H), 4.82-5.19 (m, 6H), 5.64 (br s, 2H), 6.10 (m, 1H), 6.72 (s, 1H),6.88 and 7.00 (2q, 1H total, J=5.6 Hz), 8.03 and 8.14(2d, 1H total,J=9.9Hz).

b) 1-[(1,3-bis(L-valyloxy)-2-propoxy)carbonyloxy]ethyl(7R)-3-acetoxymethyl-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylate.

A solution of the Boc-protected cefotaxime ester (247 mg) prepared as instep (a) was dissolved in 1.5 mL CH₂Cl₂ and 1.5 mL CF₃COOH. After 7 min,the solvent was removed under vacuum to give fine, light yellow solidsof the title compound as the trifluoroacetate salt.

¹H NMR (250 MHz, DMSO-d₆) δ 0.94-1.04 (m, 12H), 1.53 (d, 3H, J=5.4 Hz),2.07 and 2.08 (2s, 3H total), 2.19 (m, 2H), 3.57-3.77 (m, 2H), 3.92 (s,3H), 4.03 (br s, 2H), 4.37-4.68 (m, 4H), 4.72-4.97 (ABq, 2H), 5.18-5.27(br, 1H), 5.23 (d, 1H, J=4.9 Hz), 5.88 (m, 1H), 6.80-6.95 (m, 2H), 8.50(br s), 9.74 and 9.79 (2d, 1H total, J=8.1 Hz).

EXAMPLE A-15 4-amino-1-hydroxybutylidene-1,1-bishosphonic acid,di-(4-(L-valyloxy)benzoyloxymethyl)ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,di-(4-(N-benzyloxycarbonyl-L-valyloxy)benzoyloxymethyl)ester.

4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (141mg, 0.37 mmole) was esterified by the method described in Example A-3-a)to yield 55 mg of title compound. R_(f) (20% MeOH/CHCl₃) 0.15 (at thecenter of oval spot from baseline).

¹H-NMR (CDCl₃+1% CD₃OD): 7.82 (m, 4H), 7.29 (m, 15H), 6.97 (m, 4H), 5.85(m, 4H), 5.11 (m, 6H), 4.46 (m, 2H), 3.10 (m, 2H), 2.30-1.77 (m, 6H),1.52 (m, 6H), 0.99 (m, 12H).

³¹P-NMR (CDCl₃+1% CD₃OD)(H₃PO₄ reference): δ 15.6(s).

b) 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di-(4-(L-valyloxy)benzoyloxymethyl)ester. u

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,di-(4-(N-benzyloxycarbonyl-L-valyloxy)benzoyloxymethyl) ester is CBzdeprotected using mild conditions as prescribed in Greene, “ProtectingGroups in Organic Synthesis, (John Wiley & Sons, New York, 1981) toyield the title compound.

EXAMPLE C2 1-[1,3-bis(L-valyloxy)-2-propoxy)carbonyloxy]ethyl(Z)-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate

a)1-[(1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propoxy)carbonyloxy]ethyl(Z)-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate

A mixture of ceftizoxime sodium (550 mg, 1.36 mmol) and1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl 1-iodoethyl carbonate(1.5 mmol) in 27 mL dry DMF was stirred under nitrogen for 3 h. DMF wasremoved under vacuum and the residue was partitioned between ethylacetate and water. The organic phase was washed successively with 5%Na₂S₂O₃ and brine, stirred with anhydrous Na₂SO₄ and activated carbonfor 15 min, filtered through celite, and concentrated. Silica gel columnchromatography (2/1 petroleum ether—ethyl acetate, 20/1 CH₂Cl₂-methanol)yielded fractions enriched in the desired product. A second columnchromatography (silica, 40/1 CH₂Cl₂-methanol) gave the title compound(410 mg).

¹H NMR (250 MHz, CDCl₃) δ 0.84-0.88 (m, 6H), 0.92-0.97 (m, 6H), 1.42 (s,18H), 1.56-1.59 (m, 3H), 2.11 (br, 2H), 3.40-3.68 (m, 2H), 4.04 (s, 3H),4.17-4.51 (m, 6H), 4.97-5.14 (m, 4H), 5.73 (br s, 2H), 6.08 (m, 1H),6.66 (m, 1H), 6.76 (s, 1H), 6.85-6.95 (m, 1H), 7.93 (br d, 1H).

b) 1-[(1,3-bis(L-valyloxy)-2-propoxy)carbonyloxy]ethyl(Z)-7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate

The Boc-protected ceftizoxime ester (347 mg) from step (a) was dissolvedin 2.5 mL CH₂Cl₂ and 2.5 mL CF₃COOH. After 15 min, the solvent wasremoved under vacuum to give fine light yellow solids of the titlecompound as the trifluoroacetate salt.

¹H NMR (250 MHz, DMSO-d₆) δ 0.95-1.04 (m, 12H), 1.54 (d, 3H, J=5.4 Hz),2.20 (m, 2H), 3.64-3.66 (m, 2H), 3.88 (s, 3H), 3.97 (br s, 2H),4.37-4.66 (m, 4H), 5.15-5.20 (m, 2H), 5.87 (dd, 1H, J=8.1, 5.0 Hz), 6.67(m, 1H), 6.78 (s, 1H), 6.82 (q, 1H, 8.46 (br s), 9.54 and 9.55 (2d, 1Htotal, J=8 Hz)

EXAMPLE A-16 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di-(3-(3,4-di-(L-valyloxy)phenyl)propionyloxymethyl) ester

a) 4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,di-(3-(3,4-di(N-benzyloxycarbonyl-L-valyloxy)phenyl)propionyloxy-methyl)ester.

4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (143mg, 0.37 mmole) was esterified by the method described in Example A-3-a)to yield 169 mg of the title compound. R_(f) (20% MeOH/CHCl₃) 0.15 (atthe center of oval spot from baseline).

¹H-NMR (CDCl₃+1% CD₃OD): 7.40-6.85 (m, 31H), 5.62 (m, 4H), 5.02 (m,10H), 4.43 (m, 4H), 3.10 (m, 2H), 2.84 (m, 4H), 2.61 (m, 4H), 2.35-1.73(m, 8H), 1.52 (m, 6H), 0.99 (m, 24H). ³¹P NMR (CDCl₃+1% CD₃OD)(H₃PO₄reference): δ 14.3 (s).

b) 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di-(3-(3,4-di-(L-valyloxy)phenyl)propionyloxymethyl) ester.

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid,di-(3-(3,4-di(N-benzyloxycarbonyl-L-valyloxy)phenyl)propionyloxy-methyl)esteris CBz deprotected using mild conditions as prescribed in Greene,“Protecting Groups in Organic Synthesis, (John Wiley & Sons, New York,1981) to yield the title compound.

EXAMPLE A-17 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,tri(3-(L-valyloxy)-2,2-dimethylpropoxycarbonyloxymethyl)ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acidtri(3-(N-benzyloxycarbonyl-L-valyloxy)-2,2-dimethylpropoxycarbonyloxymethyl)ester

To a solution of4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (174mg, 0.45 mmol) in dry DMF (1 mL) were added diisopropylethylamine (240μL, 1.38 mmol), followed by3-(N-benzyloxycarbonyl-L-valyloxy)-2,2-dimethylpropyl iodomethylcarbonate (592 mg, 1.14 mmol). After stirring for 5 h at ambienttemperature, under nitrogen, the reaction mixture was concentrated on arotavapor, treated with ethyl acetate (15 mL), and filtered. The organicsolution was washed with 5% Na₂S₂O₃, followed by brine. Drying overanhydrous Na₂SO₄ and concentration gave a yellow oil that was subjectedto column chromatography (silica, 2/1 petroleum ether—ethyl acetate,2.5-20% methanol in CH₂Cl₂) to give fine, white solids (147 mg) enrichedin the triester. The solids were dissolved in ethyl acetate, washedtwice with 5% aqueous EDTA-disodium salt, dried over anhydrous Na₂SO₄,and evaporated to dryness under vacuum.

R_(f) (10% methanol in CH₂Cl₂)0.30; ¹H NMR (250 MHz, CDCl₃+1% CD₃OD) δ0.85-0.95 (m, 36 H), 1.70-2.20 (m, 7H), 3.10 (br s, 2H), 3.85-3.95 (br,12 H), 4.25 (m, 3H), 5.05 (s, 8H), 5.52-6.0 (m, 10H), 7.30 (s, 20H); ³¹PNMR (101 MHz, CDCl₃+1% CD₃OD) δ 13.6 and 24.6 (2d, J=47 Hz). The diesterwas a minor component:

³¹P NMR δ 18.6 (s).

(b) Removal of Benzyloxycarbonyl Protecting Groups

The triester (110 mg) from step (a) was hydrogenated at 40 psi over Pdblack (14 mg) in 4.2 mL solvent (2/1/1 ethyl acetate-methanol-aceticacid) for 18.5 h. The suspension was filtered through a small column ofcelite and washed with ethyl acetate-methanol. The filtrate wasevaporated to dryness under vacuum to give white solids (97 mg). Becauseproton NMR showed incomplete deprotection, the material was resubmittedfor hydrogenation (14 mg Pd, 10 mL solvent) overnight to give thedeprotected triester (as the acetate salt, 79 mg) as shown by thedisappearance of peaks for the benzyloxy group at δ 5.05 and 7.30.

³¹P NMR (101 MHz, CDCl₃) δ 12.5 and 24.0.

EXAMPLE A-18 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl)ester

a) 4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(1-(N-benzyloxycarbonyl-L-valyloxy)-2-methyl-2-propoxycarbonyloxymethyl)ester

4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (460mg, 1.2 mmol) was esterified by the method described in Example A-17 a)with 1-(N-benzyloxycarbonyl-L-valyoxy)-2-methyl-2-propyl iodomethylcarbonate (1.54 g, 3.0 mmol) for 2 h. After column chromatography(silica, 4-20% methanol in CH₂Cl₂), the pure fractions containing thetitle compound were pooled together and concentrated. The residue wasdissolved in ethyl acetate, washed twice with 5% aqueous EDTA-disodiumsalt, and then, water, dried over Na₂SO₄, and evaporated to drynessunder vacuum to give the diester as off-white solids (92 mg).

³¹P NMR (101 MHz, CDCl₃+1% CD₃OD) δ 19.5 (s); ¹H NMR (250 MHz, CDCl₃+1%CD₃OD) δ 0.76-1.41 (m, 24H), 1.74 (br s, 4H), 2.05 (m, 2H), 3.02 (br s,CH ₂N), 3.90-4.30 (m, CH ₂OC═O and CHα valine), 4.93-5.01 (m, 6H),5.30-5.90 (m, OCH ₂O and NHC═O), 7.22 (s, 15H).

b) 4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di(2-methyl-1-(L-valyloxy)-2-propoxycarbonyloxymethyl)ester

The benzyloxycarbonyl-protected diester (86 mg) from step (a) washydrogenated by the method described in Example A-17 b) to give thetitle compound (as the acetate salt) as a white powder (72 mg).

³¹P NMR (101 MHz, CDCl₃) δ 19.2 (s).

EXAMPLE A-19 4-amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(2-methyl-2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)propionyloxymethyl)ester.

a) 4-N-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(2-methyl-2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)propionyl-oxymethyl)ester

To a solution of4-benzyloxycarbonylamino-1-hydroxybutyliden-1,1-bisphosphonic acid (824mg, 2.1 mmole) and diisopropylethylamine (0.8 g, 6.3 mmole) in dryN,N-dimethylformamide (15 ml) was added dropwise a solution ofiodomethyl2-methyl-2-(N-benzyloxycarbonyl-L-isoleucyloxymethyl)propionate (3.1 g,5.21 mmole) in N,N-dimethylformamide (6 ml). The mixture was stirred 2hours at room temperature and evaporated under reduced pressure. Ethylacetate (70 ml) was added and after 1 hour the crystals were filtered.The organic phase was washed two times with saturated sodiumhydrogencarbonate solution, dried with sodium sulfate and evaporatedunder reduced pressure. The product was isolated by silica gel columnchromatography with dichloromethane/methanol. Yield: 0.36 g

¹H-NMR (CDCl₃) 0.86(m, 12H) 1.20 (m, 16H) 1.60-2.20 (m, 6H) 3.10 (m, 2H)3.80-4.40 (m, 6H) 5.08 (m, 6H) 5.45 (m, 4H) 7.29 (m, 15H)

³¹P-NMR (CDCl₃+5% CD₃OD) 14.2 (s)

b) 4-amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(2-methyl-2-(isoleucyloxymethyl)propionyloxymethyl)ester

To a solution of4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(2-methyl-2-(N-benzyloxycarbonylamino-L-isoleucyloxymethyl)propionyl-oxymethyl)ester(0.195 g, 0.171 mmole) in ethyl acetate (10 ml), methanol (10 ml) andacetic acid (5 ml) was added palladium black (100 mg). The mixture washydrogenated overnight at 45 psi. The catalyst was filtered and washedwith ethyl acetate, methanol and acetic acid. The solution wasevaporated under reduced pressure and the product was dried in vacuo toyield the title compound as the triacetate salt. Yield: 150 mg.

³¹P-NMR (CDCl₃+5% CD₃OD) 18.1 (s)

EXAMPLE A-20 4amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(4-(L-valyloxy)-cyclohexanoyloxymethyl) ester

a) 4-N-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoyloxymethyl) ester

To a solution of 4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-biphosphonic acid (0.706 g, 1.8 mmole) anddiisopropylethylamine (07 g, 5.4 mmole) in N,N-dimethylformamide (15 ml)was added dropwise a solution of iodomethyl4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoate (2.35 g, 4.5 mmole) inN,N-dimethylformamide (5 ml). The mixture was stirred 2 hours at roomtemperature under argon. The mixture was evaporated under reducedpressure. Ethyl acetate (60 ml) was added and the solid was filteredafter 2 hours. The organic phase was washed twice with saturated sodiumhydrogencarbonate and brine. The organic phase was dried with sodiumsulfate and evaporated under reduced pressure. The products wereisolated by silica gel column chromatography withdichloromethane/methanol. After silica gel column chromatography thefractions were dissolved in ethyl acetate and washed three times with 5%aqueous EDTA-disodium salt solution, dried with sodium sulfate,evaporated under reduced pressure and dried in vacuo to yield 298 mg

¹H-NMR (CDCl₃) 0.84 (m, 12H) 1.35-2.35 (m, 24H) 3.10 (m, 2H) 4.08 (m,2H) 5.02 (m, 8H) 5.55 (m, 4H) 7.24 (m, 15H) ³¹P-NMR (CDCl₃+5% CD₃OD)15.2 (s)

b) 4amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(4-(L-valyloxy)-cyclohexanoyloxymethyl) ester

4-N-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(4-(N-benzyloxycarbonyl-L-valyloxy)-cyclohexanoyloxymethyl) ester isde-CBz protected using conventional conditions as exemplified above toyield the title compound.

EXAMPLE A-21 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid tri(4-(L-valyloxy)-cyclohexanoyloxymethyl ester

The appropriate fraction of Example A-20, step a) was dissolved in ethylacetate and washed three times with 5% aqueous EDTA-disodium saltsolutions dried with sodium sulfate, evaporated under reduced pressureand dried in vacuo to yield 320 mg which is deprotected usingconventional conditions as exemplified above to yiled the titlecompound.

¹H-NMR (protected form) (CDCl₃) 0.86 (m, 18H) 1.3-2.5 (m, 34H) 3.10 (m,2H) 4.22 (m, 3H) 4.55-5.10 (m, 11H) 5.50 (m, 6H) 7.28 (m, 20H) ³¹P-NMR(CDCl₃+5% CD₃OD) 20.8 (d) 10.0 (d)

EXAMPLE A-22 4-amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(1-(L-valyloxy)-2-methylpropane-2-amino-carbonyloxymethyl) ester

a) 4-N-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(1-(N-benzloxycarbonyl-L-valyloxy)-2-methylpropane-2-amino-carbonyloxymethyl)ester

To a solution of 4-benzyloxycarbonylamino-1-hydroxybutylidene1,1-biphosphonic aid (0.1 g, 0 mmole) and diisopropylethylamine (0.31 g,2.4 mmole) in N,N-dimethylformamide (5 ml) was added dropwise a solutionof2-(N-(iodomethoxy-carbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propanein N,N-dimethylformmamide (2.5 ml). The mixture was stirred 2 hours atroom temperature under argon. The mixture was evaporated under reducedpressure. Ethyl acetate (40 ml) was added and the solid was filteredafter 2 hours. The organic phase was washed twice with saturated sodiumhydrogencarbonate and brine. The organic phase was dried with sodiumsulfate and evaporated under reduced pressure. The product was isolatedby silica gel column chromatography with dichloromethane/methanol aceticacid. After silica gel column chromatography the fractions weredissolved in ethyl acetate and washed three times with 5% aqueousEDTA-disodium salt solution, dried with sodium sulfate, evaporated underreduced pressure and dried in vacuo. Yield: 165 mg.

¹H-NMR (CDCl₃) 0.80 (m, 12H) 1.20 (m, 12H) 1.88 (m, 6H) 3.00 (m, 2H)3.64 (m 4H) 4.20 (m, 2H) 5.00 (m, 6H) 5.50 (m, 4H) 7.26 (m, 15H) ³¹P-NMR(CDCl₃+5% CD₃OD) 14.8 (s)

b) 4-amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(1-(L-valyloxy)-2-methylpropane-2-amino-carbonyloxymethyl) ester.

4-N-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(1-(N-benzloxycarbonyl-L-valyloxy)-2-methylpropane-2-amino-carbonyloxymethyl)ester is deCBz protected as exemplified above to yield the titlecompound.

EXAMPLE A-23 4-Benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi(1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethylester

a) 4-Benzyloxy carbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-(1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester

To a solution of4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic acid (565mg, 1.44 mmol) in DMF (10 mL), was added diisopropylamine (0.75 mL, 4.32mmol), followed by an injection of a solution of give1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acidiodomethyl ester (2.00 g, 3.60 mmol) in DMF (5 mL). After stirring underargon for 1.5 h at room temperature, the solution was concentrated andtreated with ethyl acetate (100 mL). Crystals were filtered off and thefiltrate was extracted with brine containing a small amount of sodiumthiosulfate. The organic phase was filtered through anhydrous sodiumsulfate and evaporated. After silica gel column (silica gel, 4→20% MeOHin CH₂Cl₂), the pure fractions containing the title compound werecombined and evaporated. The residue was then dissolved in ethyl acetateand the solution extracted twice with aqueous saturated sodiumbicarbonate and then twice with 5% aqueous EDTA-disodium salt. The ethylacetate phase was evaporated, to give 205 mg of 4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-(1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester.

¹H-NMR (CDCl₃): 8.35-7.95 (m, 2H), 7.85-7.50 (m,2H), 7.26 (br s, 15H),6.60-6.20 (m, 2H), 5.90-5.35 (m, 4H), 5.15-4.80 (m, 6H), 4.50-4.00 (m,10H), 3.18-3.00 (m, 2H), 2.45-1.55 (m, 6H), 1.00-0.80 (m, 12H). ³¹P-NMR(CDCl₃)(H₃PO₄ reference): 16.8 (s).

b) 4-amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-(1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester.

A solution of 4-benzyloxycarbonylamino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-(1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester (180 mg, 0.145 mmol) in methanol/ethyl acetate/acetic acid (2:1:1v/v/v) (20 mL) was hydrogenated over a Pd-black catalyst (30 mg) at 40psi of hydrogen for 10 h. The suspension was filtered through celite andthe filtrate was evaporated to dryness under reduced pressure, to give85 mg of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic aciddi-(1-(2-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carbonyloxymethyl)ester was obtained as a white solid.

¹H-NMR (CDCl₃): 8.65-8.20 (m, 2H), 7.95-7.65 (m, 2H), 6.65-6.30 (m, 2H),5.90-5.35 (m, 4H), 4.70-4.00 (m, 10H), 3.18-3.00 (m, 2H), 2.45-1.55 (m,6H), 1.00-0.80 (m, 12H).

³¹P-NMR (CDCl₃)(H₃PO₄ reference): 13.9 (s).

EXAMPLE P-1 (1S,2S)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea (MST-041)

a) (1S,2S)-N-{cis-2-[6-fluoro-2-(N-BOC-L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

To a solution of (1S,2S)-N-{cis-2-[6-fluoro-2-hydroxy-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea (2.03 g, 5.5 mmol) in THF (50mL) at 20° C., was added NaH (60%, 220 mg, 5.5 mmol). After the mixturewas stirred 1.5 h at 20° C., N-BOC-L-isoleucine iodomethyl ester (16.5g, 16.5 mmol) was added. The solution was stirred for 6 h at roomtemperature and then concentrated under reduced pressure. The crudeproduct was column chromatographed (aluminium oxide 90, 1% MeOH inCH₂Cl₂), to give 1.76 g of the title product.

¹H-NMR (CDCl₃): 9.75 (br s, 1H), 9.15 (br s, 1H), 8.16 (s, 1H), 7.71(dd, 1H), 7.52 (dd, 1H), 7.00-6.87 (m, 2H), 5.81 (d, 1H), 5.68 (d, 1H),5.00 (d, 1H), 4.21 (dd, 1H), 3.40-3.25 (m, 1H), 2.99-2.72 (m, 2H), 2.10(dd, 1H), 1.85-1.68 (m, 1H), 1.60-147 (m, 1H), 1.41 (s, 9H), 1.32-1.05(m, 3H), 1.13 (t, 3H), 0.88-0.78 (m, 6H).

b) (1S,2S)-N-{cis-2-[6-fluoro-2-(L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

To TFA (30 mL) at 0° C., was added (1S,2S)-N-{cis-2-[6-fluoro-2-(N-BOC-L-isoleucyloxymethyloxy)-3-propionylphenyl]cyclopropyl }-N′-[2-(5-cyanopyridyl)]urea(1.81 g, 2.96 mmol). Thereaction mixture was stirred at 0° C. for 30 min and then concentratedunder reduced pressure at 0° C. The crude product was columnchromatographed (silica gel, 10% MeOH in CRCl₂), to give 1.48 g of thetitle compound as the TFA-salt.

¹H-NMR (CDCl₃): 9.50 (br s, 1H), 9.42 (br s, 1H), 8.34 (s, 1H), 7.73(dd, 1H), 7.27 (m, 1H), 7.10 (d, 1H), 6.81 (dd, 1H), 6.16 (d, 1H), 5.73(d, 1H), 3.87 (d, 1 H), 3.39 (m, 1H), 3.05-2.68 (m, 2H), 2.29 (dd, 1H),2.10-1.88 (m, 2H), 1.57-1.21 (m, 3H), 1.09 (t, 3H), 1.02 (d, 3H), 0.91(t, 3H).

EXAMPLE P-2 (1S,2S)-N-{cis-2[6-fluoro-2-(L-valyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

a) (1S,2S)-N-{cis-2-[6-fluoro-2-(N-CBz-L-valyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

To a solution of (1S,2S)-N-{cis-2-[6-fluoro-2-hydroxy-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea (368 mg, 1 mmole) in THF (5 ml) was added sodium hydride inparaffin (60%, 38 mg, 0.95 mmole). After 1.5 hour,N-CBz-L-valyloxymethyl iodide (1.09 g, 2.8 mmole) prepared analogouslyto the N-BOC-L-isoleucyloxymethyl iodide described above was added tothe solution and reaction was kept 18 hours. The mixture was falteredthrough Celite and poured into sodium hydrogen carbonate aqueoussolution, and extracted with methylene chloride. The organic phase wasdried and the product was isolated with silica gel column chromatographyto yield 210 mg.

¹H-NMR (CDCl₃): 8.16 (s, 1H), 7.70 (dd, 1H), 7.49 (t, 1H), 7.35 (m, 5H),6.93 (m, 2H), 5.78 (dd, 2H), 5.27 (d, 1H), 5.11 (s, 2H), 4.28 (m, 1H),3.34 (m, 1H), 2.84 (m, 2H), 2.09 (m, 2H), 1.54 (m, 1H), 1.34 (m, 1H),1.10 (t, 3H), 0.87 (dd, 6H).

b) (1S,2S)-N-{cis-2-[-fluoro-2-(L-valyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

(1S,2S)-N-{cis-2-[6-fluoro-2-(N-CBz-L-valyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea(200 mg, 0.32 mmole) was dissolved in a mixed solvent of methanol (5ml), ethylacetate (2 ml) and acetic acid (1 ml). To the solution wasadded palladium black (35 mg). It was kept under hydrogen at atmosphericpressure for two hours. After filtration, the solution was evaporatedand the product was purified by silica gel column chromatographyyielding 66 mg.

¹H-NMR (CDCl₃) 8.20 (d, 1H), 7.73 (dd, 1H), 7.44 (dd, 1H), 6.94 (m, 2H),5.80 (dd, 2H), 3.37 (1H), 2.88 (m, 2H), 2.10 (m, 2H), 1.60 (m, 1H), 1.46(m, 1H), 1.08 (t, 3H), 0.94 (m, 6H).

EXAMPLE P-3 (1S,2S)-N-{cis-2[6-fluoro-2-(2,2-dimethyl-3-(L-valyloxy)-propionyloxy-methyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

a) (1S,2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-N-Boc-L-valyloxy)propionyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

To a solution of (1S,2S)-N-[cis-2-(6-fluoro-2-hydroxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)] urea (368 mg, 1 mmole) in THF (5ml) was added sodium hydride in paraffin (60%, 38 mg, 0.95 mmole). Afterone hour, 2,2-dimethyl-3-(N-Boc-L-valyloxy)propionic acid iodomethylester (1.35 g, 3 mmole) was added to the solution. After 5 hr at roomtemperature, it was then raised to 50° C. and reaction was kept 18hours. The reaction mixture was poured into sodium hydrogen carbonateaqueous solution and extracted with methylene chloride. The organicphase was dried and the product was isolated with alumina columnchromatography. 140 mg.

¹H-NMR (CDCl₃): 8.39-6.70 (m, 5H) 5.77 (m, 2H ) 5.15 (d, 1H) 4.00 (m,3H) 3.40 (m, 1H) 2.90 (m, 2H) 2.30 (m, 1H) 2.20 (m, 1H) 1.70 (m, 1H)1.42 (s, 9H) 1.16 (d, 6H) 0.92 (m, 9H)

b) (1S,2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-(L-valyloxy)propionyl-oxymethyloxy)-3-propionylphenyl]-cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

(1S,2S)-N-{cis-2-[6-fluoro-2-(2,2-dimethyl-3-(N-Boc-L-valyloxy)-propionyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)] urea (120 mg) was treated withtrifluoroacetic acid at 0° C. for 20 min. The solution was evaporatedand coevaporated with toluene and methanol succesively, giving thetitled product in quantitative yield.

¹H-NMR (CDCl₃): 8.33 (d, 1H) 7.89 (d, 1H) 7.48 (t, 1H) 7.16 (m, 1H) 6.96(t, 1H) 5.70 (dd, 2H) 4.18 (dd, 2H) 4.01 (m, 1H) 3.38 (m, 1H) 2.88 (m,2H) 2.16 (m, 1H) 1.58 (m, 2H) 1.25 (d, 6H) 1.04 (m, 9H).

EXAMPLE P-4 (1S,2S)-N-{cis-2-[6-fluoro-2-(3,3-bis-(L-valyloxyethyl)propionyloxymethyloxy)-3-propionylphenyl)]cycloloropyl}-N′-[2-(5-cyanopyridyl)]urea

a) (1S, 2S)-N-{cis-2-[6-fluoro-2-(3,3-bis (N-CBz-L-valyloxymethyl)propionyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

To a solution of (1S,2S)-N-{cis-2-[6-fluoro-2-hydroxy-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)] urea (331 mg, 1 mmole) in THF (5ml) was added sodium hydride in paraffin (60%, 32 mg, 0.81 mmole). Afterone hour, 3,3-bis-(N-CBz-L-valyloxymethyl) propionic acid iodomethylester (1.3 g, 1.8 mmole) was added to the solution. After 5 hr at roomtemperature, it was then raised to 50° C. and reaction was kept 18hours. The mixture was poured into sodium hydrogen carbonate aqueoussolution, and extracted with methylene chloride. The organic phase wasdried and the product was isolated with alumina column chromatography.185 mg.

¹H-NMR (CDCl₃): 8.19 (s, 1H) 7.89 (dd, 1H) 7.32 (m, 11H) 7.10 (m, 1H)6.90 (t, 1H) 5.79 (dd, 2H) 5.09 (s, 2H) 4.31 (m, 2H) 4.08 (m, 4H) 2.95(m, 2H) 2.50 (m, 3H) 2.17 (m, 3H) 1.55 (m, 1H) 1.07 (t, 3H) 0.88 (dd, 12H).

b) (1S, 2S)-N-{cis-2-[6-fluoro-2-(3,3-bis(L-valyloxymethyl)propionyloxy-methyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

(1S, 2S)-N-{cis-2-[6-fluoro-2-(3,3-bis (N-CBz-L-valyloxymethyl)propionyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea (170 mg, 0.17 mmole) was dissolved in a mixed solvent of methanol(5 ml), ethyl acetate (2 ml) and acetic acid (1 ml). To the solution wasadded palladium black (30 mg). It was kept under hydrogen at atmosphericpressure for four hours. After filtration, the solution was evaporatedand the product was purified by silica gel column chromatography. 80 mg.

¹H-NMR (DMSO-d6): 8.38 (d, 1H) 8.02 (d, 1H) 7.42 (m, 2H) 7.12 (t, 1H)5.70 (dd, 2H) 4.00 (s, 4H) 3.16 (m, 1H) 3.08 (d, 2H) 2.80 (m, 1H) 2.40(m, 2H), 2.11 (m, 1H) 1.52 (m, 1H) 0.95 (t, 3H) 0.98 (dd, 12 H).

EXAMPLE P-5 (1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-valyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

a) (1S,2S)-N-{cis-2-[6-fluoro-2-(2-(N-CBz-L-valyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

To a solution of (1S, 2S)-N-{cis-2[6-fluoro-2-hydroxy-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea (368 mg, 1 mmole) in THF (5 ml)was added sodium hydride in paraffin (60%, 38 mg, 0.95 mmole). After 1.5hr, 2-(N-CBz-L-valyloxy)ethoxycarbonyloxymethyl iodide (864 mg, 1.7mmole) was added to the solution. The reaction was kept for 48 hours.The mixture was poured into sodium hydrogen carbonate aqueous solution,and extracted with methylene chloride. The organic phase was dried andthe product was isolated with silica gel column chromatography. 210 mg.

¹H-NMR (CDCl₃): 8.21 (d, 1H) 7.72 (d, 1H) 7.28 (m, 6H) 6.90 (m, 2H) 5.75(dd, 2H) 5.09 (s, 2H) 4.35 (m, 4H) 2.85 (m, 2H) 2.50 (m, 2H) 2.16 (m,1H), 1.65 (m, 1H) 1.11 (t, 3H) 10.93 (dd, 6 H).

b) 1S,2S)-N-{cis-2-[6-fluoro-2-(2-(L-valyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

(1S,2S)-N-{cis-2-[6-fluoro-2-(2-(N-CBz-L-valyloxy)-ethoxycarbonyloxymethyloxy)-3-propionylphenyl)]cyclopropyl)}-N′-[2-(5-cyanopyridyl)]urea is deprotected by conventional techniques such as palladium blackin a mixed solvent of methanol, ethyl acetate and acetic acid underhydrogen at atmospheric pressure followed by conventional work up suchas filtration, evaporation and silica gel column chromatography.

EXAMPLE P-6 (1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-L-valyloxy-2-(propoxycarbonyloxymethyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea

a)(1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-(N-BOC-L-valyloxy-2-(propoxycarbonyloxymethloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea.

NaH (121 mg, 60% w/w in mineral oil, 3.0 mmol) was added to a mixture of(1S,2S)-N-[cis-2-(6-fluoro-2-hydroxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea(1.05 g, 2.85 mmol) in 15 mL dry THF under N₂. After 1 h, the solutionwas concentrated to dryness and redissolved in 10 ML DMF2-O-iodomethoxycarbonyl-1,3-di-O-(N-tert-butoxycarbonyl-L-valyl)glycerol(2.96 g, 4.39 mmol) in 15 mL DMF was added and the reaction mixture wasstirred for 20 h. Removal of solvent under vacuum followed by flashcolumn chromatography (silica gel, 2/1 ethyl acetate-petroleum ether)gave 1.46 g (56%) of the title product as a white solid.

¹H NMR (250 MHz, CD₃OD) δ 0.94 and 0.97 (2d overlap, 12H), 1.11 (t, 3H),1.23 (m, 1H), 1.46 (s, 18H), 1.64 (m, 1H), 2.07-2.24 (m, 3H), 2.90 (m,2H), 3.32 (m, 1H), 4.06 (d, 2H), 4.28-4.52 (m, 4H), 5.13 (m, 1H), 5.78and 5.88 (AB q, 2H), 7.07-7.19 (m, 2H), 7.62 (dd, 1H), 7.92 (dd, 1H),8.31 (d, 1H).

b)(1S,2S)-N-[cis-2-(6-fluoro-2-(1,3-bis-L-valyloxy-2-(propoxycarbonyloxymethyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea

Ice-cold trifluoroacetic acid (30 mL) was added to the intermediate ofstep a (1.69 g, 1.85 mmol) in an ice bath, under N₂. After 7 min, thereaction mixture was concentrated under vacuum, coevaporating severaltimes with, initially, toluene and, finally, CH₂Cl₂. The oily residuewas chromatographed immediately on a silica gel column with 10-20%methanol in CH₂Cl₂ to give 1.37 g of the product as a trifluoroacetatesalt.

¹H NMR (250 MHz, CD₃OD) δ 1.07-1.12 (m, 15H), 1.26 (m, 1H), 1.63 (m,1H), 2.19 (m, 1H), 2.35 (m, 2H), 2.89 (m, 2H), 4.08 (m, 2H), 4.44-4.71(m, 4H), 5.26 (m, 1H), 5.79 and 5.91 (AB q, 2H), 7.10-7.18 (m, 2H), 7.59(dd, 1H), 7.93 (dd, 1H), 8.30 (d, 1H).

¹⁹F NMR (235 MHz, CD₃OD) δ −103.5, −73.5.

EXAMPLE P-7(1S,2S)-N-[cis-2-(6-fluoro-2-(L-valyloxy)methoxycarbonyloxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl]urea

a)(1S,2S)-N-[cis-2-(6-fluoro-2-chloromethoxycarbonyloxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea

Chloromethyl chloroformate (2.3 mL, 25 mmol) was added by syringe to amixture of(1S,2S)-N-[cis-2-(6-fluoro-2-hydroxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea(4.695 g, 12.7 mmol) and pyridine (6.1 mL, 76 mmol) in 65 mL dry CH₂Cl₂with cooling in an ice bath, under N₂. After 10 min, the ice bath wasremoved and the mixture was stirred at room temperature for 1 h 40 min.The mixture was diluted with 100 mL CH₂Cl₂ and washed with 50 mL H₂O.The aqueous phase was reextracted with 25 mL CH₂Cl₂. The combinedorganic phases were washed with 50 mL saturated NaHCO₃, followed by 2×50mL brine. Drying over Na₂SO₄ and concentration under vacuum gave a crudematerial that was subjected to flash column chromatography (silica gel,1/1 ethyl acetate-petroleum ether) to give 4.05 g (69%) title product.

¹H NMR (250 MHz, CDCl₃) δ 1.15 (t, 3H), 1.30 (m, 1H), 1.59 (m, 1H), 2.02(m 1H), 2.87 (q, 2H), 3.29 (m, 1H), 5.87 (s, 2H), 6.97 (d, 1H), 7.09 (m,1H), 7.72 (dd, 1H), 7.76 (dd, 1H), 8.10 (dd, 1H), 9.26 (br s, 1H), 10.09(brs, 1H).

b)(1S,2S)-N-[cis-2-(6-fluoro-2-iodomethoxycarbonyloxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea

(1S,2S)-N-[cis-2-(6-fluoro-2-chloromethoxycarbonyloxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea (3.97 g, 8.6 mmol) and NaI(5.17 g, 34.5 mmol) in 85 mL dry acetonitrile were refluxed at 70° C.for 4 h under N₂. The solvent was removed in vacuo, the residue waspartitioned between 100 mL CH₂Cl₂ and 25 mL H₂O, the aqueous phase wasreextracted with 10 mL CH₂Cl₂, and the organic phases were combined,washed successively with 2×25 mL 5% Na₂S₂O₃ and 2×25 mL brine, and driedover Na₂SO₄. Flash column chromatography (silica gel, 2/1 ethylacetate-petroleum ether) of the crude product obtained afterconcentration in vacuo gave 4.15 g material containing 92% of the titlecompound and traces of the starting material.

¹H NMR (250 MHz, CDCl₃) δ 1.18 (t, 3H), 1.34 (m, 1H), 1.62 (m, 1H), 2.03(m, 1H), 2.86 (q, 2H), 3.32 (m, 1H), 6.08 (s, 2H), 6.97 (d, 1H), 7.08(m, 1H), 7.70-7.76 (m, 2H), 8.13 (d, 1H), 8.90 (br s, 1H), 9.30 (br s,1H).

c)(1S,2S)-N-[cis-2-(6-fluoro-2-(N-BOC-L-valyloxy)methoxycarbonyloxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea

Tetrabutylammonium hydroxide (40 wt % solution in water, 6.4 mL, 9.8mmol) was added to Boc-L-valine (2.54 g, 11.7 mmol) in 30 mL dioxane.The solution was concentrated in vacuo, coevaporating several times withdioxane, toluene, and CH₂Cl₂, and dried under vacuum overnight. Theresulting Q salt was dissolved in 30 mL dry CH₂Cl₂ and(1S,2S)-N-[cis-2-(6-fluoro-2-(iodomethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea(7.1 mmol) in 65 mL dry CH₂Cl₂ was added. After stirring under N₂ for 18h, the reaction mixture was washed with 3×50 mL H₂O, 1×50 mL 5% Na₂S₂O₃,and 2×50 mL H₂O. The organic phase was dried over Na₂SO₄, concentrated,and submitted to flash column chromatography (silica gel, 3/1 ethylacetate-petroleum ether) to give 2.21 g (49%) product.

¹H NMR (250 MHz, CD₃OD) δ 0.98 (d, 3H), 1.02 (d, 3H), 1.17 (t, 3H), 1.24(m, 1H), 1.47 (s, 9H), 1.59 (m, 1H), 2.06 (m, 1H), 2.24 (m, 1H), 2.96(q, 2H), 3.24 (m, 1H), 4.15 (d, 1H), 5.94 and 6.02 (AB q, 2H), 7.12 (d,1H), 7.26 (m, 1H), 7.91 (dd, 1H), 7.94 (dd, 1H), 8.23 (dd, 1H).

d) (1S,2S)-N-[cis-2-(6-fluoro-2-(Lvalyloxy)methoxycarbonyloxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea

Cold trifluoroacetic acid (40 mL) was added to(1S,2S)-N-[cis-2-(6-fluoro-2-(N-BOC-L-valyloxymethoxycarbonyloxy)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea(1.94 g, 3.02 mmol) with cooling in an ice bath, under N₂. After 5 min,the solution was concentrated in vacuo, coevaporating several times withtoluene, and then CH₂Cl₂, and dried under vacuum for several hours togive the compound as a trifluoroacetate salt in quantitative yield.

¹H NMR (250 MHz, CD₃OD) δ 1.12-1.18 (m, 9H), 1.25 (m, 1H), 1.59 (m, 1H),2.07 (m, 1H), 2.47 (m, 1H), 2.97 (q, 2H), 3.26 (m, 1H), 4.16 (d, 1H),6.01 and 6.37 (AB q, 2H), 7.11 (d, 1H), 7.29 (m,1H), 7.92 (dd, 1H), 7.99(dd, 1H), 8.22 (d, 1H).

¹⁹F NMR (235 MHz, CD₃OD) δ −102.7, −74.0.

EXAMPLE P-8 (1S,2S)-N-{cis-2[6-fluoro-2-(3-carboxylpropionyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

a) (1S,2S)-N-{cis-2-[6-fluoro-2-(3-benzyloxycarbonylpropionyl-oxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

3-Benzyloxycarbonylpropionic acid iodomethyl ester (522 mg, 1.5 mmole)was added to a solution of (1S,2S)-N-{cis-2-[6-fluoro-2-hydroxy-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)] urea (185 mg, 0.5 mmole) in THF (5ml) which had been treated with sodium hydride in paraffin (60%, 20 mg,0.5 mmole) for 30 min. After 18 hr at room temperature, the reactionmixture was poured into sodium hydrogen carbonate aqueous solution, andextracted with methylene chloride. The organic phase was dried and theproduct was isolated with alumina column chromatography. 115 mg.

¹H-NMR (CDCl₃): 8.20 (d, 1H) 7.72 (dd, 1H) 7.49 (dd, 1H) 7.35 (m, 5H)6.97 (m, 2H) 5.73 (dd, 2H) 5.17 (s, 2H) 3,35 (m, 1H) 2.88 (m, 2H) 2.60(m, 4H) 2.12 (m, 1H) 1.58 (m, 1H) 1.11 (t, 3H).

b) (1S,2S)-N-{cis-2-[6-fluoro-2-(3-carboxylpropionyloxymethyloxy)-3-propionylphenyl]cyclopropyl}-N′-[2-(5-cyanopyridyl)]urea

(1S,2S)-N-{cis-2-[6-fluoro-2-(3-carboxylpropionyloxymethyloxy)-3-propionylphenyl)]cyclopropyl}-N′-[2-(5cyanopyridyl)]urea (100 mg, 0.17 mmole) was dissolved in a mixed solvent ofethylacetate (3 ml) and acetic acid (1 ml). To the solution was addedpalladium black (30 mg). It was kept under hydrogen at atmosphericpressure for three hours. After filtration, the solution was evaporatedand the product was purified by silica gel column chromatography. 81 mg.

¹H-NMR (CDCl₃): 8.21 (s, 1H) 7.75 (d, 1H) 7.49 (dd, 1H) 7.08 (d, 5H)6.97 (t, 1H) 5.73 (dd, 2H) 5.17 (s, 2H) 3.26 (m, 1H) 2.87 (m, 2H) 2.60(m, 4H) 2.09 (m, 1H) 1.58 (m, 1H) 1.11 (t, 3H)

EXAMPLE P-9 (1S,2S)-N-[cis-2-(6-fluoro-2-O-(4-L-valvyloxcybenzoyl)-3propionylphenyl)-cyclopropyl]-N′-(5-cyanopyridyl-2-yl)urea

a) 4-benzyloxybenzoic acid.

To a solution of 4-hydroxybenzoic acid (6.9 g, 50 mmole) in 150 ml DMFwas added potassium tert.-butoxide (12.34 g, 110 mmole) and the mixturewas stirred at room temperature for one hour. Benzyl bromide (20.5 g,120 mmole) was added and the mixture was stirred for two days at roomtemperature. The mixture was evaporated under reduced pressure and 100ml 1,4-dioxane and a solution of sodium hydroxide (6.0 g, 150 mmole)in50 ml water was added. The mixture was refluxed for two hours, cooledand evaporated under reduced pressure. Water was added and the mixturewas acidified with acetic acid. The product was filtered, washed withcold water and dried. Yield: 10.2 g=89%.

b) 4-benzyloxybenzoyl chloride.

To a mixture of 4benzyloxybenzoic acid (2.28 g, 10 mmole) in 20 ml drieddichloromethane were added five drops of DMF and 2.5 ml thionylchloride. The mixture was refluxed for three hours and evaporated underreduced pressure. Yield: 2.45 g=100%

c) (1S,2H)-N-[cis2-(6-fluoro-2-O-(4benzyloxybenzoyl)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl-2-yl)urea.

To a solution of (1S,2S)-N-[cis-2-(6-fluoro-2-hydroxy-3-propionylphenyl)cyclopropyl]-N′-(5-cyanopyridyl-2-yl) urea (184 mg, 0.5 mmole) in 3 mlDMF was added potassium text. butoxide (78.5 mg, 0.7 mmole) and themixture was stirred for one hour at room temperature. A solution of4-benzyloxybenzoylchloride (185 mg, 0.75 mmole) in 1 ml DMF was addedand the mixture was stirred overnight at room temperature. 40 ml ethylacetate were added and the organic phase was washed four times withwater. The solution was dried with sodium sulfate and evaporated underreduced pressure. The product was isolated by silica gel columnchromatography.

Yield: 180 mg=62%.

¹H-NMR (DMSO δ-6) 0.92 (m, 4H) 1.31((m, 1H) 1.85 (m, 1H) 2.82 (m, 2H)3.06 (m, 1H) 5.26 (s, 2H) 7.20 (m 2H) 7.38-8.12 (m, 11H) 8.38 (m, 1H)

d) (1S, 2S)-N-[cis-2-(6-fluoro-2-O (4-hydroxybenzoyl)-3-propionylphenyl)cyclopropyl]-N′-(5-cyanopyridyl-2-yl)] urea-O-4-hydroxybenzoate

A solution of the intermediate of step c) (170 mg, 0.29 mmole) in 15 mlethyl acetate and 15 ml methanol was hydrogenated with 10% palladium oncharcoal (30 mg) three times at room temperature and normal pressure.The catalyst was filtered and washed with ethyl acetate and methanol andthe solution was evaporated under reduced pressure. The product wasisolated by silica gel column chromatography. Yield: 100 mg=70%.

¹H-NMR (DMSO δ-6) 0.93 (m, 4H) 1.32 (m, 1H) 1.88 (m,1H) 2.85 (m, 2H)3.05 (m, 1H) 6.92 (m, 2H) 7.38 (m, 2H) 8.00 (m, 4H) 8.38 (m, 1H)

e) (1S, 2S)-N-[cis-2-(6-fluoro-2-O(4-L-valyloxybenzoyl)-3-propionylphenyl)-cyclopropyl]-N′-(5-cyanopyridyl-2-yl)urea

An R₂ group, such as N-protected L-valyl is acylated to the exposed ringhydroxy group using conventional acylation conditions as describedherein and deprotected to yield a compound of the invention.

EXAMPLE P-10 (1S, 2S)-N-[cis-2-(6-fluoro-2-O((4-isoleucyloxybenzoyloxymethyl)-3-propionylphenyl)-cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea-O-methylene4-hydroxybenzoate-O-L-isoleucylester

a) Methyl-4-(4-methoxybenzyloxy) benzoate.

To a solution of methyl 4-hydoxybenzoate (6.85 g, 45 mmole) in 80 ml DMFwas added potassium tert. butoxide (5.6 g, 51 mmole) and the mixture wasstirred at room temperature for one hour. 4-Methoxybenzyl chloride (8.3g, 52 mmole) was added and the mixture was stirred overnight at roomtemperature. The mixture was evaporated under reduced pressure and 200ml ethyl acetate was added. The organic phase was washed four times withwater, dried with sodium sulfate and evaporated under reduced pressure.Yield: 12.3 g=100%

¹H-NMR (CDCl₃) 3.82 (s, 3H) 3.88 (s, 3H) 5.03 (s, 2H) 6.96 (m, 4H) 7.36(d, 2H) 7.98 (d, 2H)

b) 4-(4-methoxybenzyloxy) benzoic acid

To a solution of methyl 4-(4-methoxybenzyloxy) benzoate (12.2 g, 44.8mmole) in 50 ml 1,4-dioxane was added a solution of lithium hydroxide(2.15 g, 89.6 mmole) and the mixture was stirred overnight at 60° C. Themixture was evaporated under reduced pressure and 5% acetic acid wasadded. The product was filtered, washed with water and dried. Yield:10.1 g=87%

¹H-NMR (DMSO δ-6) 3.74 (s, 3H) 5.08 (s, 2H) 6.92 (d, 2H) 7.06 (d, 2H)7.36 (d, 2H) 7.90 (d, 2H)

c) Chloromethyl 4-(4methoxybenzyloxy)benzoate

To a solution of 4-(4-methoxybenzyloxy) benzoic acid (5.16 g, 20 mmole)in 100 ml 1,4-dioxane was added a 40% solution of tetrabutylammoniumhydroxide (14.27 g, 22 mmole) and the mixture was stirred 2 hours atroom temperature. The mixture was evaporated under reduced pressure andco-evaporated two times with 1,4-dioxane and two times with toluene. Thedried product was dissolved in 60 ml dichloromethane andiodochloromethane (35.3 g 200 mmole) was added. The solution was stirredfor two days at room temperature and evaporated under reduced pressure.About 100 ml ethyl actate was added and the organic phase washed twicewith water, dried with sodium sulfate and evaporated under reducedpressure. The product was isolated by silica gel column chromatography.Yield: 4.48 g=73%

¹H-NM (CDCl₃) 3.83 (s, 3H) 5.06 (s, 2H) 5.94 (s, 2H) 7.00 (m, 4H) 7.36(d, 2H) 8.05 (d, 2H)

d) Iodomethyl 4-(4-methoxybenzyloxy) benzoate

To a solution of chloromethyl 4-(4-methoxybenzyloxy) benzoate (0.77 g,2.5 mmole) in 15 ml dry acetone was added sodium iodide (1.87 g, 12.5mmole) and the mixture was stirred overnight at room temperature. Themixture was evaporated under reduced pressure and extracted with ethylactate/water. The organic phase was washed with a 5% sodium thiosulfatesolution, dried with sodium sulfate and evaporated under reducedpressure. Yield 0.86 g=86%

¹H-NMR (CDCl₃) 3.84 (s, 3H) 5.05 (s, 2H) 6.14 (s, 2H) 6.98 (m, 4H) 7.36(d, 2H) 8.00 (d, 2H)

e) (1S,2S)-N-[cis-2-(6-fluoro-2-O-(4(4-methoxybenzyloxy)-benzoyloxymethyl)-3-propionylphenyl(cyclopropyl]-N′-[2-(5-cyanopyridyl)urea

To a solution of (1S,2S)-N-[cis-2-(6-fluoro-2-hydroxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea (368 mg, 1 mmole) in 5 ml DMFwas added a suspension of 60% sodium hydride in mineral oil (44 mg, 1.1mmole) and the mixture was stirred for one hour at room temperature. Asolution of iodomethyl-4-(4-methoxybenzyloxy) benzoate (0.84 g, 2.1mmole) in 2 ml THF was added and the mixture was stirred overnight atroom temperature. 50 ml ethyl acetate were added and the organic phasewas washed four times with water, dried with sodium sulfate andevaporated under reduced pressure. The product was isolated by silicagel column chromatography. Yield: 525 mg=82%

¹H-NMR (CDCl₃) 0.91 (m, 3H) 1.32 (m, 1H) 1.60 (m, 1H) 2.04 (m, 1H) 2.90(m, 2H) 3.20 (m, 1H) 3.82 (s, 3H) 5.04 (s, 2H) 5.84-6.06 (m, 2H)6.91-8.18 (m,13H)

f) (1S, 2S)-N-[cis-2-(6-fluoro-2-O(4-hydroxybenzoyloxymethyl)-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea-O-methylene-4-hydroxybenzoate

To a solution of the intermediate of step e) (100 mg, 0.156 mmole) in 4ml dichloromethane was added TFA (0.5 ml) and the solution was stirredfor one hour at room temperature. The solution was evaporated underreduced pressure and the product was isolated by silica gel columnchromatography. Yield: 45 mg 55%.

¹H-NMR (DMSO δ-6) 0.84 (m, 3H) 1.10 (m, 1H) 1.48 (m, 1H) 2.12 (m, 1H)2.80 (m, 2H) 3.19 (m, 1H) 5.85-6.02 (m, 2H) 6.84 (m, 2H) 7.18 (m, 1H)7.46 (m, 2H) 7.74 (m, 2H) 8.04 (m, 2H) 8.38 (m, 1H)

g) (1S, 2S)-N-[cis-2-(6-fluoro-2-O(4-isoleucyloxybenzoyloxymethyl)-3-propionylphenyl)-cyclopropyl]-N′-[2-(5-cyanopyridyl)]urea-O-methylene-4-hydroxybenzoate-O-L-isoleucylester

An R₂ group, such as N-protected L-isoleucine is acylated to the exposedhydroxy group using conventional acylation condtions as described hereinand deprotected to yield a compound of the invention.

BIOLOGICAL EXAMPLE 1 Pharmacokinetics

Confirmation that orally administered prodrugs of the invention releaseFLG in vivo is obtained in a rat model which is recognized as a usefulmodel for assessing pharmacokinetic parameters of nucleoside analogues.The oral compositions are administered in a pharmaceutical vehiclecomprising propylene glycol, or in the case of the more solublecompounds such as that of Example 26 or Example 34, in water, toduplicate fasted animals in a dosage corresponding to 0.1 mmol/kg. Forcomparison, a set of rats is iv dosed with 0.01 mmol/kg of themetabolite 2′,3′-dideoxy-3′-fluoroguanosine. Serum levels of themetabolite are then monitored in serum collected at intervals fromindividual animals from 0.5 to up to 12 hours following administration(5 min to 6 hours for FLG).

The metabolite is analysed with HPLC with UV detection at 254 nm, in amanner analogous to Stahle et al 1995, J Pharm. Biomed. Anal. 13,369-376. An HPLC system can be based on a 0.05 Mammonium-dihydrogen-phosphate buffer, with 1.2% 2-propanol solvent,buffered to pH 4.5 or 30 mM sodium dihydrogen phosphate buffer with 2%acetonitrile solvent buffered to pH 7.0. The column may be a 100×2.1 mmBAS C18 5 μm particle size with a 7 μm C18 guard column or Zorbax SB-CNC18 150×4.6 mm, 5 μm column. Protein binding of the compounds of theinvention is neglible as is that of the metabolite and ultrafiltrationthrough Amicon or Microcon 30 filters is useful for serum samples.Advantageously the main peak is subject to further column chromatographyto better aid in resolution of FLG over low weight serum components. Theiv levels are multiplied by a factor of ten in order to obtain AUCvalues for comparison with the oral values. Absolute oralbioavailability is determined as the ratio between ⁰⁻⁰⁵AUC_(IV) and⁰⁻⁰⁵AUC_(oral).

TABLE 1 6 h absolute 12 h absolute bioavail. % bioavail. % FLG   9%**Example 22 39% >80%* Example 13 37% Example 12 29% Example 25 81.5%  Example 28 47.5%   Example 24 60.5%   Example 26 67.5%   Example 29 51%*estimated. **literature value

The compounds of the invention thus provide significantly enhanced oralbioavailability relative to the metabolite metabolite2′,3′-dideoxy-3′-fluoroguanosine. Notably, the compounds are releasedinto the blood in a relatively sustained manner, rather than in animmediate peak. This means that effective amounts of the activemetabolite are available in the blood for many hours assisting oncedaily dosage. Additionally, a sustained release avoids the problems ofacute toxicity seen in compounds with a more rapid release rate.

Although the rat is well recognized as a good model for predicting humanbioavailability of nuceoide analogues, species independentbioavailability of a compound of the invention (Example 34) wasconfirmed in ≅11.5 kg male and female beagle dogs administered orallywith 0.05 mmol/kg (38 mg/kg) compound in water or iv 0.005 mmol/kg (1.35mg/kg) metabolite in water. Plasma collection and analysis as above.

Male dog 12 hour absolute bioavailability 51% Female dog 12 hourabsolute bioavailability 74%

BIOLOGICAL EXAMPLE 2 Antiviral Activity—Retroviruses

As can be demonstrated by the methodology of Biological Example 1, thecompounds of the invention release, in vivo, the metabolite2′,3′-dideoxy,3′-fluoroguanosine. In vitro measurement of the antiviralactivity of this metabolite will thus reflect the de facto activity ofthe compounds of the invention.

In the XTT dye uptake assay of Koshida et al Antimicrob AgentsChemother. 33 778-780, 1989) utilising MT4 cells, the metabolitemeasured in Biological Example 1 above showed the following in vitroactivities against retroviruses:

TABLE 2 HIV or retroviral strain IC₅₀* HIV-1_(111B)   1 μg/ml HIV-1²⁴⁴¹AZT′   1 μg/ml HIV-1_(111B) TIBO′   1 μg/ml HIV-1^(29/9) 0.7 μg/mlHIV-2_(SBL6669)   2 μg/ml SIV_(SM)   1 μg/ml *Concentration ofmetabolite inducing 50% inhibition of viral replication

It will thus be apparent that administration of the compounds of theinvention induce powerful antiviral activities against the retrovirusesHIV-1, HIV-2 and SIV. It should also be noted from the HIV-1²⁴⁴¹ AZT^(f)and HIV-1_(111B) TIBO′ results that the antiviral activity of thecompounds of the invention does not show cross resistance againststrains of HIV which have become resistant to other HIV agents such asthe nucleoside analogue AZT or or the non-nucleoside reversetranscriptase inhibitor TIBO.

BIOLOGICAL EXAMPLE 3 Antiviral Activity—HBV

The activity of antivirals on duck hepatitis B virus (DHBV) in ducks isan acknowledged animal model for the validation of in vivo hepatitis Bactivity in humans. The activity of the in vivo metabolite measured inBiological Example 2 above has been assayed in the DHBV model describedby Sherker et al (1986) Gastroenterology 91, pp 818-824. The results aredepicted in FIGS. 1 and 2 In short, 4 control ducks were treated withphosphate buffered saline (PBS) and 4 ducks with 5 mg/kg/day of theactive metabolite. The ducks were two days old when inoculated with DHBVand 18 days old when treatment was commenced. The metabolite and PBS(controls) were given intraperitoneally for 10 days as twice dailyinjections, at 8 am and 4 pm. Treatment lasted 33 days and the animalswere followed 5 weeks after the end of treatment.

The efficacy of treatment was followed by dot blot-hybridisation of DHBVDNA in serum using a radioactive probe and the amount of DHBV measuredas the amount of radioactivity hybridised. FIG. 1 plots the amount ofDHBV DNA in serum at different timepoints before, during and aftertreatment.

As can be seen in FIG. 1, there is no decrease in the amount of DHBV inserum during treatment with PBS (control, solid line). The animals giventhe metabolite measured in Biological Example 2 (broken line) showed adramatic decrease in the amount of DHBV in serum during the first 10days of treatment, whereupon for the remainder of treatment the level ofDHBV DNA was below the detection limit at this dose of 5 mg/kg/day.Repeat experiments at dosages of 30 and 3 mg/kg/day and withcongenitally infected ducks (not shown) also produced similar results,that is a dramatic fall in serum DHBV DNA to under the detectionthreshold. Even at the very low dose of 0.3 mg/kg/day the metabolitecaused a considerable inhibition of DHBV in vivo. After the finish oftreatment, virus reappeared in the serum, as shown in FIG. 1.Reappearance of HBV after short term treatment with conventionalantivirals has been observed earlier in both humans and animals withchronic hepatitis B infection.

As can be seen in FIG. 2, the weight of the ducks increased in the sameway as in the control (PBS treated) animals. The weight increase fromabout 270 g to about 800 g which was observed during the treatmentperiod is so large that toxic effects, had they occurred, should beeasily visible as a change in growth rate. Similar growth curves werealso observed for the ducks receiving the higher dosage rate of 30mg/kg/day. This metabolite is thus clearly non-toxic. As the compoundsof the invention are hydrolysed in vivo to give this metabolite, asestablished in Example 2 above, and a nature identical and thereforeeasily metabolized fatty acid, it can therefore be inferred that no longterm toxicity problem can be expected from adminstration of thecompounds of the invention. The absence of acute (short term) toxicityof the compounds of the invention when administered orally isestablished in Biological Example 2 above.

BIOLOGICAL EXAMPLE 4 Bioavailability

The release of a compound of Formula P-2 from orally administeredprodrugs of Formulae P3 to P8 were monitored in rats. The compounds ofExamples P1 to P6 were made up in a propylene glycol vehicle and orallyadministered to paired fasted male Sprague Dawley rats at a dosecorresponding to 0.027 mmol/kg. At 30, 60, 120, 240 & 360 minutes, 0.2ml blood were collected, centrifuged and frozen for later analysis. Thereleased drug of Formula P-2, (1S,2S)-N-[cis-2-(6-fluoro-2-hydroxy-3-propionylphenyl)cyclopropyl]-N′-[2-(5-cyanopyridyl)] urea was assayed by HPLC. Aliquotscomprising 40-100 μl of each plasma sample are mixed with an equalvolume of acetonitrile (10 seconds, Vibrofex). The sample is centrifuged(2 min, 14000 RPM) and 30 μl of the supernatant is injected into an HPLCsystem, as follows.

Pre column: RP-18, 7 μm, 15 × 3.2 mm Column: YMC basic, 3 μm, 150 × 3 mmMobile phase: 60% acetonitrile in 3 mM ammonium acetate, pH 6.4 Flowrate: 0.4 ml/min Detection: UV, 250 nm

TABLE P-1 Example Bioavai1abi1ity_(0-6 hours) P-1 34% P-2 18% P-3 27%P-4 18% P-6 50% P-7 70%

The above bioavailabilities correspond to sustained plasma levels of theactive metabolite well above the ED₅₀ for HIV-1.

BIOLOGICAL EXAMPLE 6

Bioavailability of the ring indanolic ring hydroxy compound of ExampleB-1 was assessed in rats by the procedure of Biological Example 5 alsousing a propylene glycol vehicle, 58 mg/kg (0.047 mmol/kg), but whereinthe mother compound N1, N6-di[(1S,2R)-2-hydroxy-2,3-dihydro-1-H-1-indenyl]-(2R, 3R,5R)-2,5-di(benzyloxy)-3,4-dihydroxyhexanediamide was assayed by LC-MSusing SiM (single ion monitoring) with M/Z ion detector 653, Plasmaresults are presented as μM in the table below

Time Rat 1 Rat 2 Rat 3 0 <0.02   <0.02   <0.02   0.5 0.17 0.46 0.23 10.73 1.4  1.22 2 0.86 1.7  1.09 4 0.52 0.67 0.43 6 0.23 0.24 0.08

The average bioavailability is thus 57%. This should be contrasted withthe bioavailability of the mother compound (below level of detection).Interestingly the bioavailability of the analogue bearing groups(depicted immediately below) but lacking the linker component of theinvention was also below the level of detection in the same assay:

BIOLOGICAL EXAMPLE A-1

The bioavailability of a prodrug of the invention built on thebis-phosphonate alendronate was assayed in rats.4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid,di-(2-methyl-2-(L-valyloxymethyl)propionyloxymethyl) ester and thealendronate mother compound were orally administered at a dosecorresponding to 0.1 mmol/kg to respective paired rats in a propyleneglycol vehicle.

Urine was collected over 24 hours in a metabolic cage and analysed asshown in Kline et al J Chromat. 534 (1990) 139-149, but modified asfollows: 1 ml of urine is mixed with 50 μl or 1.25 M calcium chlorideand 100 μl of 1M sodium hydroxide. After centrifugation, the urine wasaspirated off and the pellet redissolved in 0.8 ml 0.2 M acetic acid,0.4 ml of 0.01 M EDTA and 0.4 ml of 0.2 m sodium acetate. 1 mlof waterwas added and the solution loaded onto a preconditioned DEA cartridge.The cartridge was washed with 1 ml of water and alendronate eluted with1 ml of 1M carbonate buffer, pH 10.4. A part of the eluent, 150 μl wasmixed with 5 μl of 0.05 M potassium cyanide and 5 μl of NDA solution (1mg/ml) in methanol. 50 μl was injected into the chromatograph.

The compound of the invention exhibited a 28-30 fold improvementrelative to the bioavailabilty of alendronate itself.

1. A method for treatment of HBV or HIV infections comprisingadministering to an individual in need thereof an effective amount ofthe compound of formula IId′

wherein R₂ is the residue of an aliphatic L-amino acid, p is 0, 1 or2-20, and q is 0, or a pharmaceutically acceptable salt thereof.
 2. Themethod according to claim 1, wherein R₂ is the residue of isoleucine orin said compound.
 3. The method according to claim 2, wherein saidcompound is selected from the group consisting of2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-butyryl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-hexanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-octanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-decanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-dodecanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-myristoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-palmitoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-stearoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-docosanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-eicosanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-butyryl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-hexanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-octanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-decanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-dodecanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-myristoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-palmitoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-stearoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-docosanoyl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-butyryl] guanosine,2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-eicosanoyl] guanosineand pharmaceutically acceptable salts thereof.
 4. The method accordingto claims 1, wherein p is 0 in said compound.
 5. The method according toclaim 4, wherein said compound is denoted2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-propionyl] guanosine; or2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-isoleucyloxy)-propionyl] guanosine,wherein the propionyl moiety has the configuration of L-lactic acid, andpharmaceutically acceptable salts thereof.
 6. The method according toclaim 4, wherein said compound is denoted2′,3′-dideoxy-3′-fluoro-5′-O-[2-(L-valyloxy)-propionyl] guanosine,wherein the propionyl moiety has the configuration of L-lactic acid, andpharmaceutically acceptable salts thereof.
 7. The method of claim 1,wherein said compound is administered in an amount of 50 to 1,500 mg. 8.The method of claim 1, wherein said compound is administered in anamount of 100 to 700 mg.
 9. The method of claim 1, wherein said compoundis administered once, twice or three times per day.
 10. The method ofclaim 1, wherein said blood serum level of said active metabolite of thecompound of formula IId′ is 0.01 to 100 μg/ml.
 11. The method of claim10, wherein said blood serum level of said active metabolite is 0.01 to5 μg/ml.
 12. The method of claim 1, wherein the retroviral infection isHIV.
 13. The method of claim 6, wherein the retroviral infection is HIV.